Compounds with high monoamine transporter affinity

ABSTRACT

Featured compounds have high monoamine transport affinity and are characterized by one of the following two general formulas set out above. The compounds bind selectively or non-selectively to monoamine transporters. The compounds are useful to treat various medical indications including attention deficit hyperactivity disorder (ADHD), Parkinson&#39;s disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.09/691,396, a continuation-in-part of PCT Application No. PCT/US01/32575having an international filing date of Oct. 17, 2001 and published inEnglish under PCT Article 21(2) and a continuation-in-part ofprovisional application Ser. No. 60/401,836, filed Aug. 6, 2002, theentire teachings of which are incorporated herein by reference.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The U.S. Government may have certain rights in this invention pursuantto Grant Nos. NIDA RO1 DA11542, and NIDA NO1 DA7-8081, awarded by NIDA(N1H).

TECHNICAL FIELD

This invention relates to novel compositions with affinity for amonoamine transporter, such as the dopamine, norepinephrine, orserotonin transporter, in brain and in peripheral tissues.

BACKGROUND OF THE INVENTION

Monoamine transporters play a variety of roles, and compounds withaffinity for the monoamine transporters have been proposed for therapyand/or diagnosis of medical indications that include (but are notlimited to) attention deficit hyperactivity disorder (ADHD), Parkinson'sdisease, cocaine addiction, smoking cessation, weight reduction,obsessive-compulsive disorder, various forms of depression, traumaticbrain injury, stroke, and narcolepsy.

The dopamine transporter (DAT) in particular is a primary mechanism forterminating the effects of synaptic dopamine and maintaining homeostaticlevels of extracellular dopamine in brain. Giros et al., Nature 379:606-612 (1996). The dopamine transporter is a principal target oftherapeutic and psychostimulant drugs of abuse. For example, thedopamine transporter is an important target of drugs (includingmethylphenidate, pemoline, amphetamine and bupropion) used to treatADHD. Seeman and Madras, Mol. Psychiatry 3:386-396 (1998); Cyr andBrown, Drugs, 56:215-223 (1998); Biederman, J. Clin. Psychiatry 59: 4-16(1998); Riggs et al., J Am Acad. Child Adolesc. Psychiatry 37:1271-1278(1999). The dopamine transporter is also a principal target of brainimaging agents used, for example, diagnostically.

It has been suggested that the therapeutic benefit of benztropin(Cogentin®) for Parkinson's disease results in part from blockingdopamine transport thereby increasing synaptic dopamine. Coyle andSnyder, J. Pharmacol. Exp. Ther., 170:221-319 (1969).

The antidepressant bupropion apparently is also a monoamine transportinhibitor [Hirschfeld, J. Clin. Psychiatry 17: 32-35 (1999)], and it hasbeen suggested as a treatment to aid smoking cessation. Jorenby et al.,N. Engl. J. Med., 340:685-691 (1999); McAfee et al., N. Engl. Med.,338:619(1998).

The dopamine transporter has been identified as an effective marker fordopamine terminals in Parkinson's disease. Kaufman and Madras, Synapse9: 43-49 (1991). Brain imaging of the transporter in humnans withParkinson's disease and in animals with experimentally producedParkinsonism has confirmed the usefulness of the dopamine transporter inthis application. Fischman et al., Synapse 29: 128-141, 1998, Seibyl etal., Ann. Neurol. 38:589-598.

The serotonin transporter (SERT) regulates extracellular serotoninlevels. It is a principal target of effective drugs (known asserotonin-selective reuptake inhibitors or SSRI's) used to treatmelancholic depression, atypical depression, dysthymia andobsessive-compulsive disorder. It also is a conduit of entry intoserotonin containing neurons of neurotoxic substituted amphetamines.Selective imaging agents that label the serotonin transporter would beuseful to investigate the status of the transporter in depression[Malison et al. Bio. Psychiatry 44:1090-1098 (1998)], alcoholism [Heinzet al. Am. J. Psychiatry 155:1544-1549 (1998)], obsessive-compulsivedisorder, and substituted amphetamine abusers [McCann et al., Lancet352:1433-1437 (1998); Semple et al., Br., J. Psychiatry 175: 63-39(1999)]. There are various reports generally dealing with individualserotonin transporter imaging agents. Acton et al. Eur. J. Nucl. Med.26:1359-1362 (1999); Szabo et al. J. Cereb. Blood Flow Metab. 19:967-981(1999); Oya et al. J. Med. Chem. 42:333-335 (1999).

Norepinephrine regulates mood, is involved in learning and memory, andcontrols endocrine and autonomic functions. Dysfunction ofnorepinephrine neurotransmission has been implicated in depression,cardiovascular and thermal pathophysiology. The norepinephrinetransporter (NET) regulates extracellular levels of norepinephrine inbrain, in heart, and in the sympathetic nervous system. Clinically, thenorepinephrine transporter is a principal target of selective ornon-selective anti-depressant drugs and stimulant drugs of abuse such ascocaine and amphetamines. Blockade of the norepinephine transporter isimplicated in appetite suppression. Gehlert et al. J. Pharmacol. Exp.Ther. 287:122-127 (1998). Imaging of the norepinephrine transporter mayalso be useful for viewing the status of sympathetic innervation in theheart and in other adrenergic terminals, and for detectingneuroblastomas. Hadrich et al. J. Med. Chem. 42:3010-3018 (1999); Raffelet al., J. Nucl. Med. 40:323-330 (1999).

It is desirable to avoid unwanted side effects of treatments targetingmonoamine transporters, to the extent possible. It is also desirable toproduce efficient and effective diagnostics for various conditionsinvolving monoamine transporters.

SUMMARY OF THE INVENTION

The invention features compounds of two general classes that have highand selective monoamine transport affinity. Featured compounds of thefirst class (which we term oxaindanes) generally have the followingformula:

WHERE:* indicates a chiral center, and each chiral center, independently, maybe R, S, or R/S;—X≡CH₂R₁; —CHR₁R₅; —CR₁═O; —CR₆═O; —O—R₁; —SR₁; —SOR₆; —SO₂R₆;

-   -   —SO₂NHR₁; or —CH═CR₁R₅ and where:        -   a. —R₁ and —R₅ are independently selected from: —H; —CH₃;            —CH₂CH₃; or —CH₂(CH₂)_(m)CH₃, where m=0, 1, 2, or 3;            -   PROVIDED THAT, when X≡O—R₁, then R₁≠H;                -   and        -   b. —R₆ is selected from: —OH; —OCH₃; —NHR₁; —O-alkyl;            —O-alkenyl; —O-alkynyl; —O-allyl; —O-iodoallyl; -alkyl;            -alkenyl; -alkynyl; -allyl; -isopropyl; and -isobutyl;            —Ar=either    -   a) phenyl substituted at any two positions with R_(3a) and        R_(3b), where R_(3a) and R_(3b) are as defined in options “I.”        or “II.”, below; or    -   b) 1-napththyl or 2-naphthyl, substituted at any two positions        with R_(3a), and R_(3b) where R_(3a) and R_(3b) are as defined        in option “I.”, below);        -   OPTION I for R_(3a) nd R_(3b) (phenyl or naphthyl            substitutions)        -   —R_(3a) and —R_(3b) are independently selected from: —H;            —Br; —Cl; —I; —F; —OH; —OCH₃; —CF₃; —NO₂; —NH₂; —CN;            —NHCOCH₃, —C(CH₃)₃, —(CH₂)_(q)CH₃ where q=0-6; —COCH₃; —F            (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4            position); —I (at the 2, 3 or 4 position); alkynyl; alkenyl;            alkynyl; allyl; iospropyl; isobutyl; alkyl;            -alkylN₂S₂chelator; -alkylN₂S₂Tc chelator, such that N₂S₂ is            part of a chelating moiety such as those known in the art            which contain two nitrogens and two sulfur atoms, in            addition to carbon and optionally other heteroatoms, see,            for example, O'Neil et al., Bioconjugate Chem., 5:182-193            (1994); O'Neil et al., Inorgan. Chem., 33:319-323(1994);            Kung et al., J. Nucl. Med. 27:1051 (1986); Kung et al., J.            Med. Chem. 28:1280-1284 (1985), hereby incorporated by            reference; or COR₇, where R₇ is defined below;        -   OPTION II. for R_(3a), and R^(3b) (phenyl substitutions)        -   —R_(3a) and —R_(3b) as a pair are independently selected            from the following pairs: 3,4-diCl; 3,4,diOH; 3,4-diOAc;            3,4-diOCH₃; 3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; or 3-F, 4-OH;            n=0 or 1;

-   —R₂═H, —COOCH₃; —COR₇; -alkyl; -alkenyl; -allyl; -iodoallyl;    -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN₂S₂ chelator-;    —O-alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; —O-alkylN₂S₂Tc    chelator; where,    -   —R₇ is=—NHR₈; morpholinyl; piperidinyl; —CH₃; —CH₂CH₃;        —CH₂(CH₂)_(r)CH₃ where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl;        allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH₂SO₂;        -alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; O-alkylN₂S₂        chelator; or —O-alkylN₂S₂Tc chelator; and    -   —R₈ is=-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl;        -isoxazole; oxadiazole; -oxazole; -alkylN₂S₂ chelator;        —O-alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; or —O-alkylN₂S₂Tc        chelator;

-   R_(4a) and R_(4b) are independently selected from:    -   —H; —Br; —Cl; —I; —F; —OH; —OCH₃; —CF₃; —NO₂; —NH₂; —CN;        —NHCOCH₃, C(CH₃)₃, —(CH₂)_(q)CH₃ where q=O-6; —COCH₃; —F (at the        2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (at the        2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl;        isobutyl; alkyl; -alkylN₂S₂; -alkylN₂S₂Tc; and COR₇, where R₇ is        defined above; or

-   R_(4a) and R_(4b) are selected as a pair from the following pairs:    -   3,4-diCl; 3,4-diOH; 3,4-diOAc; 3,4-diOCH₃; 3-OH, 4-Cl; 3-OH,        4-F; 3-Cl, 4-OH; and 3-F, 4-OH.

Preferred substituents for the above general formula are as follows: nis preferably 0; X is preferably —O—R₁, where R₁ is preferably —CH₃; Aris preferably phenyl or napthyl (1- or 2-napththyl), substituted at anytwo positions with R_(3a), and R_(3b); e.g., R_(3a) and R_(3b) mayindependently be —Cl, —H. Particularly preferred compounds are O-1617;O-1630; O-1833; O-1925, described below in Table 2.

The second general class of compounds (which we generally termtetrahydropyranyl esters or THP esters) generally have one of thefollowing three formulas:

Where:n is 0, 1, 2, or 3;

-   >X is >CH₂; >CHY; >C(YZ); >C═O; >O; >S; >SO; >SO₂; >NSO₂; >NSO₂R₃;    or >C═CYZ;    -   where Y and Z are independently selected from H; Br; Cl; I; F;        OH; OCH₃; CF₃; NO₂; NH₂; CN; NHCOCH₃; N(CH₃)₂; (CH₂)_(m)CH₃,        where m=0-6; COCH₃; alkyl alkenyl, alkynyl, allyl, isopropyl,        isobutyl;        —Ar=either    -   a) phenyl substituted at any two positions with ^(and R) _(1b),        where R_(1a) and R_(1b) are as defined in options “I.” or “II.”,        below; or    -   b) 1-napththyl or 2-naphthyl, substituted at any two positions        with R_(1a) and R_(1b) where R_(1a) and R_(1b) are as defined in        option “I.”, below);        OPTION I for R_(1a), and R_(1b) (phenyl or naphthyl        substitutions)    -   —R_(1a) and —R_(1b) are independently selected from: —H; —Br;        —Cl; —I; —F; —OH; —OCH₃; —CF₃; —NO₂; —NH₂; —CN; —NHCOCH₃,        —C(CH₃)₃, —(CH₂)_(q)CH₃ where q=0-6; —COCH₃; —F (at the 2, 3 or        4 position), —Cl (at the 2, 3 or 4 position); —I (at the 2, 3 or        4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl;        isobutyl; alkyl; -alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; or        COR₄, where R₄ is defined below;        OPTION II. for R_(1a), and R_(1b) (phenyl substitutions)    -   —R_(1a) and —R_(1b) as a pair are independently selected from        the following pairs: 3,4-diCl; 3,4,diOH; 3,4-diOAc; 3,4-CH₃;        3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; or 3-F, 4-OH; —R₂=—COOCH₃;        —COR₄; -alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl;        -isoxazole; -oxadiazole; -oxazole; -alkylN₂S₂ chelator;        —O-alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; —O-alkylN₂S₂Tc        chelator; or        where,    -   —R₄ is=—NHR₅; morpholinyl; piperidinyl; —CH₃; —CH₂CH₃;        —CH₂(CH2)_(r)CH₃ where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl;        allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH₂SO₂;        -alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; O-alkylN₂S₂        chelator; or —O-alkylN₂S₂Tc chelator; and    -   —R₅ is=-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl;        -isoxazole; -oxadiazole; -ox azole; -alkylN₂S₂ chelator;        —O-alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; —O-alkylN₂S₂Tc        chelator, and        R₉ and R₁₀ are independently ═H, CH₃, CH₂CH₃, (CH₂)_(r)CH₃,        (CH₂)_(r)C₆H₃YZ, isopropyl, isobutyl, CH═CH—(CH₂)CH₃,        CH₂CH═CH(CH₂)_(r)CH₃, (CH₂)_(n)CH═CH(CH₂)_(r)CH₃, C        C(CH₂)_(r)CH₃, CH₂C C(CH₂)_(r)CH₃, where r=0-6 and s=0-6 and Y        and Z are independently ═H, F, Cl, Br, I, OH, OR, CH₃, CF₃,        amino, NO₂.

In one preferred compounds are those with the following substituents: Xis preferably 0; n is preferably 1; preferably the compound has formulaA, above; R₂ is preferably —COR₄, most preferably —COOCH₃; —Ar ispreferably phenyl substituted at any two positions with R_(3a), andR_(3b), e.g., where R_(3a), and R_(3b) are independently selected from—H and —Cl. R₄ is —OCH₃ or —C₂H₅. Particularly preferred compounds arecompounds: 1a (compound O-1793), 1b (compound O-1792), 2a (compoundO-1794), 2b (compound O-1783), and the corresponding carboxylic acids,3a, 3b, 4a, or 4b.

In another embodiment, X is preferably C; n is preferably 1; preferablythe compound has formula A, above; R₂ is —COOCH₃; —Ar is preferablyphenyl substituted at any two positions with R_(3a), and R_(3b), e.g.,where R_(3a), and R_(3b) are independently selected from —H and —Cl.Examples of preferred compounds includeα-cyclohexyl-3,4-dichlorobenzylcyanide andα-cyclohexyl-3,4-dichlorophenylcyclohexyl acetic acid methyl ester.

In another embodiment, X is preferably C; n is preferably 0 (the ring isa cyclopentyl group); preferably the compound has formula A, above; R₂is preferably —COOCH₃; —Ar is preferably phenyl substituted at any twopositions with R_(3a), and R_(3b), e.g., where R_(3a), and R_(3b) areindependently selected from —H and —Cl. Examples of preferred compoundsinclude α-cyclopentyl-3,4-dichlorobenzylcyanide andα-cyclopentyl-3,4-dichlorophenylcyclohexyl acetic acid methyl ester,compounds 10 and 11, respectively.

As noted above, other embodiments include compounds in which R₂ is animine function such as:

This function is synthesized from the corresponding ketone by standardtechniques using the appropriate amine. The resulting imines showincreased bioavailability and surprising stability under the temperatureand pH conditions of the stomach. See, Palani et al., J. Med. Chem.44:3339 (2001).

Compounds of the above formula which demonstrate monoamine transportaffinity are useful for labeling receptor-expressing cells using invitro techniques that are generally known to those skilled in the fieldand are generally described below. They may also be used for in vivoimaging in the conditions described above and to treat various medicalindications, including attention deficit hyperactivity disorder (ADHD),Parkinson's disease, cocaine addiction, smoking cessation, weightreduction, obsessive-compulsive disorder, various forms of depression,traumatic brain injury, stroke, and narcolepsy. A more exhausive list ofmedical indications where the compounds have diagnostic or therapeuticutility includes: depression and related disorders, seasonal affectivedisorders, sexual dysfunction, sexual behavior disorders, attentiondeficit hyperactivity disorder, learning deficit, senile dementia,disorders involving the release of acetylcholine, including memorydeficits, dementia of aging, AIDS-dementia, senile dementia,pseudodementia, presenile dementia), autism, mutism, cognitivedisorders, dyslexia, tardive dyskinesia, hyperkinesia, anxiety, panicdisorders, paranoia, obsessive-compulsive disorder, post-traumaticsyndrome, social phobia, other phobias, psychosis, bipolar disorder andother psychiatric or clinical disfunctions, mania, manic depression,schizophrenia (deficient form and productive form) and acute or chronicextrapyramidal symptoms induced by neuroleptic agents, obsessivecompulsive disorders (OCD), chronic fatigue syndrome, for enhancingalertness, attention, arousal and vigilance, narcolepsy, disorders ofsleep, jet-lag, obesity, bulimic and other eating disorders, anorexianervosa, cocaine and other drug addiction or misuse, alcoholism, tobaccoabuse, neurological disorders including epilepsy, traumatic braininjury, treatment of neurodegenerative diseases, including Parkinson'sDisease, Alzheimer's Disease, Huntington's Disease, Amyotrophic LateralSclerosis, Gilles de la Tourette's syndrome, the treatment of mild,moderate or even severe pain of acute, chronic or recurrent character,as well as pain caused by migraine, postoperative pain, and phantom limbpain, disorders linked to decreased transmission of serotonin inmammals, including Ganser's syndrome, migraine headache, pre-menstrualsyndrome or late luteal phase syndrome, and peripheral neuropathy.

The invention also includes methods of making medicaments for treatingthe above indications, as well as pharmaceutical compositions comprisingthe compounds formulated to treat those indications, e.g., with apharmaceutically acceptable carrier.

The invention also includes method of using the above compoundsdiagnostically or in research (e.g., using scanning techniques such asPET or DAT) to determine physiological conditions associated withaltered function distribution number or density of dopaminenorepinephrine or serotonin transporters which lead to behavioral andneuordegenerative disorders or diseases such as those listed above. Inthat case the compounds typically will be labeled by substituting anatom with one of its corresponding radioisotope (e.g., substitute H with³H, or F with ¹⁸F). Alternatively, the compounds a radioactivesubstituent may be added to the compound.

The details of one or more embodiments of the invention are set forth inthe accompanying structures and the description below. Other features,objects, and advantages of the invention will be apparent from thefollowing description and structures, and from the claims.

DETAILED DESCRIPTION OF THE FIGURES

FIG. 1 shows the synthesis of 3-aryl substituted oxaindanes.

FIG. 2 shows synthesis of aryltetrhydropyranyl methyl esters (Scheme 1).

FIG. 3 shows synthesis of threo- anderythro-3,4-dicholorophenyltetrahydropyran-2-yl acetic acid (Scheme 2).

FIG. 4 shows resolution of threo-3,4-dicholorophenyltetrahydropyran-2-ylacetic acid (Scheme 3).

FIG. 5 shows resolution of erythro-3,4-dicholorophenyltetrahydropyran-2-yl acetic acid (Scheme 4).

FIG. 6 shows synthesis of 3,4-dicholorophenylcycloalkyl acetic acidmethyl esters (Scheme 5).

DETAILED DESCRIPTION

The compounds according to the invention are detailed above and in theclaims. Formulation into pharmaceuticals, and use of thosepharmaceuticals are detailed below. In therapeutic applications, thecompound may be administered with a physiologically acceptable carrier,such as physiological saline. The therapeutic compositions of theinvention can also contain a carrier or excipient, many of which areknown to skilled artisans. Excipients that can be used include buffers(e.g., citrate buffer, phosphate buffer, acetate buffer, and bicarbonatebuffer), amino acids, urea, alcohols, ascorbic acid, phospholipids,proteins (e.g., serum albumin), EDTA, sodium chloride, liposomes,mannitol, sorbitol, and glycerol. The compounds of the invention can beformulated in various ways, according to the corresponding route ofadministration. For example, liquid solutions can be made for ingestionor injection; gels or powders can be made for ingestion, inhalation, ortopical application. Methods for making such formulations are well knownand can be found in, for example, “Remington's Pharmaceutical Sciences.”

Routes of administration are also well known to skilled pharmacologistsand physicians and include intraperitoneal, intramuscular, subcutaneous,rectal and intravenous administration. Additional routes includeintracranial (e.g., intracistemal or intraventricular), intraorbital,opthalnic, intracapsular, intraspinal, intraperitoneal, transmucosal,topical, subcutaneous, and oral administration. It is expected that theoral route will be preferred for the administration of the compounds.The subcutaneous route may also be used. Another route of administrationof the compounds that is feasible is the intraperitoneal route. Systemicadministration of the compounds can also be effective. Thus, while onemay target the compounds more specifically to their site of action, suchtargeting is not necessary for effective treatment.

It is well known in the medical arts that dosages for any one patientdepend on many factors, including the general health, sex, weight, bodysurface area, and age of the patient, as well as the particular compoundto be administered, the time and route of administration, and otherdrugs being administered concurrently. Dosages for the compound of theinvention will vary, but can, when administered intravenously, be givenin doses of approximately 0.01 mg to 100 mg/ml blood volume. A dosagecan be administered one or more times per day, if necessary, andtreatment can be continued for prolonged periods of time, up to andincluding the lifetime of the patient being treated. If a compound ofthe invention is administered subcutaneously, the dosage can be reduced,and/or the compound can be administered less frequently. Determinationof correct dosage for a given application is well within the abilitiesof one of ordinary skill in the art of pharmacology. In addition, thoseof ordinary skill in the art can turn to data and experiments presentedbelow for guidance in evaluating the binding properties of compounds,e.g., when developing an effective treatment regime. Additionally, onecould begin tailoring the dosage of the compounds required for effectivetreatment of humans from the dosage proven effective in the treatment ofsmall mammals. Routine experimentation would be required to moreprecisely define the effective limits of any given administrativeregime. For example, in a conservative approach, one could define thelowest effective dosage in small mammals, and administer that dose toprogressively larger mammals before beginning human safety trials.

This invention will be illustrated further by the following examples.These examples are not intended to limit the scope of the claimedinvention in any manner. The Examples provide suitable methods forpreparing compounds of the present invention. However, those skilled inthe art may make compounds of the present invention by any othersuitable means. As is well known to those skilled in the art, othersubstituents can be provided for the illustrated compounds by suitablemodification of the reactants.

I. Synthesis of Oxaindanes

The following general description relates to the synthesis of theoxaindane analogs.

CIS- AND TRANS-1-METHOXY-3-ARYL-INDANS

The general synthesis of the 3-aryl substituted oxaindanes wasaccomplished via the route presented in the scheme for the 3-naphthylanalogs shown below. The synthesis of the four isomers (twodiastereomers 7 and 10, and a pair of enantiomers of each, a and b), wasaccomplished via an intermediate described by Bøgesø, K. P. et al., J.Med. Chem. 28, 1817-1828 (1985). Thus, the cis diastereomers 6a and 6bwere prepared in five steps from 2-bromobenzaldehyde. These cis alcohols6a and 6b were then methylated with sodium hydride and methyl iodide toprovide the target cis-methoxyindans 7a and 7b. Inversion ofstereochemistry at the C-1 position was accomplished via Mitsunobuinversion by reaction with benzoic acid in the presence of triphenylphosphine and diethylazodicarboxylate to provide the trans enantiomers8a and 8b (only one enantiomer is shown in the scheme in FIG. 1).Methylations, as for alcohols 6a and 6b, then provided the targettrans-methoxyindans 10a and 10b.

EXPERIMENTAL SECTION

Experimental details for the above general synthesis follow.

NMR spectra were recorded in CDCl₃ on a JEOL 300 NMR spectrometeroperating at 300.53 MHz for ¹H, and 75.58 MHz for ¹³C. TMS was used asinternal standard. Melting points are uncorrected and were measured on aGallenkamp melting point apparatus. Thin layer chromatography (TLC) wascarried out on Baker Si250F plates. Visualization was accomplished witheither UV exposure or treatment with phosphomolybdic acid (PMA). Flashchromatography was carried out on Baker Silica Gel 40 mM. Elementalanalyses were performed by Atlantic Microlab, Atlanta, Ga. All reactionswere conducted under an inert (N2) atmosphere.

Ethyl 2-cyano-3-(2-bromophenyl)-2-propenoate, 2

2-Bromobenzaldehyde-1 (10.0 g, 54.0 mmol), ethyl cyanoacetate (6.91 g,61.1 mmol) and piperidine (0.11 mL, 1.08 mmol) in toluene (45 mL) wererefluxed at 135° C. with a Dean-Stark trap for 3 h. The solvent wasremoved on a rotary evaporator. The residue was crystallized fromisopropyl ether to give 2 as a white powder (12.0 g, 75%): R_(f) 0.3(10% EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 8.63 (s, 1H), 8.17 (dd, 1H, J=8, 2Hz), 7.70 (dd, 1H, J=8, 1 Hz), 7.35-7.49 (m, 2H), 4.32 (q, 2H, J=7 Hz),1.41 (t, 3H, J=7 Hz).

Ethyl 3-(2-bromophenyl)-3-(2-naphthyl)-2-cyanopropanoate, 3

Magnesium (90 mg, 3.66 mmol) was added into a solution of2-bromonaphthalene (0.76 g, 3.66 mmol) and dibromoethane (37 TL, 0.43mmol) in THF (15 mL). The reaction was stirred at room temperature for30 min, and 1 h at 70° C. The reaction was then cooled to roomtemperature, followed by the addition of ethyl2-cyano-3-(2-bromophenyl)-2-propenoate, 2 (1.00 g, 3.05 mmol). Thereaction mixture was then refluxed at 70° C. overnight. 3N HCl (3 mL)and H₂O (5 mL) were added dropwise. The water layer was extracted withether (3×30 mL). The organic solvent was removed on a rotary evaporator.The residue was purified by flash chromatography (20% EtOAc/hexanes) toafford 0.87 g (63%) of 3 as a colorless oil: R_(f) 0.46 (10%EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 7.72-7.96 (m, 4H), 7.63 (td, 1H, J=9, 1Hz) 7.24-7.52 (m, 5H), 7.1-7.2 (m, 1H), 5.45-5.49 (m, 1H), 4.40 (dd, 1H,J=12, 8 Hz), 4.01-4.21 (m, 2H), 1.08 (dt, 3H, J=22, 7 Hz).

3-(2-Bromophenyl)-3-(2-naphthyl)propanoic acid, 4

Ethyl 3-(2-bromophenyl)-3-(2-naphthyl)-2-cyanopropanoate, 3 (0.84 g,1.84 mmol), glacial acetic acid (10 mL), conc. H₂SO₄ (5 mL), and H₂O (5mL) were refluxed at 100° C. for 24 h. The reaction mixture was pouredinto ice and extracted with EtOAc (2×40 mL). The organic solvent wasremoved on a rotary evaporator. The crude solid was stirred in 3M KOH (5mL) for 30 min. The basic aqueous solution was extracted with CHCl₃(3×10 mL). The basic aqueous solution was acidified with 3N HCl to pH4.The acidic solution was then extracted with EtOAc (3×20 mL). The organicsolvent was removed on a rotary evaporator to give 4 (0.47 g, 72%) as awhite solid: R_(f) 0.4 (40% EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 7.69-7.79(m, 4H), 7.54 (dd, 1H, J=8, 1 Hz), 7.40-7.48 (m, 2H), 7.33 (dd, 1H, J=9,2 Hz), 7.17-7.25 (m, 2H), 7.02-7.08 (m, 1H), 5.18 (t, 1H, J=8 Hz), 3.13(d, 2H, J=8 Hz).

3-(2-Naphthyl)indanone, 5

n-BuLi (2.5 M in hexane, 1.2 mL, 2.91 mmol) was added dropwise into asolution of 3-(2-bromophenyl)-3-(2-naphthyl) propanoic acid, 4 (0.47 g,1.32 mmol) at −10° C. The reaction mixture was stirred at 0° C. in anice bath for 4 h. 3N HCl (2 mL) and H₂O (3 mL) were added. The H₂O layerwas extracted with ether (3×20 mL). The organic solvent was removed on arotary evaporator. The residue was purified by flash chromatography (20%EtOAc/hexanes) to afford 5 (155 mg, 45%) as a colorless oil: R_(f) 0.46(10% EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 7.84 (d, 1H, J=8 Hz), 7.71-7.77(m, 3H), 7.62 (d, 1H, J=1 Hz), 7.36-7.52 (m, 4H), 7.22 (dd, 1H, J=8, 1Hz), 7.08 (dd, 1H, J=8, 2 Hz), 4.66 (q, 1H, J=4 Hz), 3.23 (dd, 1H, J=19,8 Hz), 2.74 (dd, 1H, J=19, 4 Hz).

Cis-3-(2-Naphthyl)indan-1-ol, 6a and 6b

K-Selectride (1M in THF, 1.20 mL, 1.20 mmol) was added into a solutionof 3-(2-naphthyl)indanone, 5 (155 mg, 0.60 mmol) at 0° C. The reactionwas stirred at 0° C. for 4 h. H₂O (5 mL) was added and the reactionmixture was extracted with ether (3×20 mL). Ether was removed on arotary evaporator. ¹H-NMR of the crude residue confirmed the structure.The crude residue was used for next step without further purification.

Cis-3-(2-Naphthyl)-O-methylindanol, 7a and 7b

Sodium hydride (60% dispersion, 80 mg, 2.15 mmol) was added into asolution of cis-3-(2-naphthyl)-indan-1-ol 6a and 6b (140 mg, 0.538 mmol)and methyl iodide (0.13 mL, 2.15 mmol) in THF (3 mL). The reactionmixture was stirred overnight. H₂O (4 mL) was added and the reactionmixture was extracted with ether (3×20 mL). The organic solvent wasremoved on a rotary evaporator. The residue was purified by flashchromatography (10% EtOAc/hexanes) to afford 0.10 g (68%) of 7a and 7bas a colorless oil: R_(f) 0.57 (10% EtOAc/hexanes); ¹H-NMR (CDCl₃) δ7.75-7.80 (m, 3H), 7.71 (s, 1H), 7.38-7.58 (m, 3H), 7.25-7.32 (m, 2H),7.20 (td, 1H, J=7, 1 Hz), 6.93 (d, 1H, J=7 Hz), 4.95 (t, 1H, J=7 Hz),4.34 (t, 1H, J=8 Hz), 3.51 (s, 3H), 2.99 (qd, 1H, J=7, 6 Hz), 2.09 (qd,1H, J=7, 6 Hz).

Trans-Benzoic acid 3-(2-naphthyl)indan-1-yl esters, 8a and 8b

Triphenylphosphine (1.44 g, 5.49 mmol) and benzoic acid (0.60 g, 4.91mmol) were added to a solution of cis-3-(2-naphthyl)-indan-1-ol, 6a and6b (0.645 g, 2.48 mmol) in anhydrous THF (20 mL). The reaction wastreated dropwise with a solution of DEAD in THF (4.95 M, 1 mL) thenstirred under nitrogen atmosphere at room temperature. After 3 h, thereaction solution was directly filtered through a pad of silica andcondensed. The resulting residue was purified by radial chromatography(4 mm plate, 10% ethyl acetate/hexanes) yielding a mixture ofenantiomers 8a and 8b as an off-white solid (0.72 g, 80%): R_(f=)0.46 in10% ethyl acetate/hexanes; ¹H-NMR (CDCl₃) δ 8.08-8.05 (m, 2H), 7.84-7.78(m, 3H), 7.71 (bs, 1H), 7.58-7.41 (m, 4H), 7.35-7.29 (m, 2H), 7.24 (dd,2H, J=5.7, 2.7), 7.07-7.04 (m, 1H), 6.62 (dd, 1H, J=6.3, 1.9), 4.88 (t,1H, J=7.7), 2.83 (ddd, 1 H, J=2.2, 7.7, 14.6), 2.69-2.60 (ddd, 1H,J=6.6, 7.98, 14.6).

Trans-3-(2-Naphthyl)indan-1-ol, 9a and 9b

Trans-3-(2-Naphthyl)indan-1-benzoate esters, 8a and 8b (0.681 g, 1.87mmol) were dissolved in THF (60 mL) and methanol (35 mL) was added.Aqueous potassium hydroxide (3M, 10 mL) was added and the reactionsolution was stirred vigorously at room temperature for 1.5 h until nostarting material was detected by TLC. The methanol was removed in vacuoand the remaining solution was acidified to pH=3 with 3 M HCl (aq). Theaqueous solution was extracted with ether (3×50 mL) and the combinedorganic layers were concentrated in vacuo. The residue was purified byradial chromatography (4 mm plate, 30% ethyl acetate/hexanes) to providethe enantiomers 9a and 9b as a clear oil (0.347 g, 71%) which foamedunder high vacuum: R_(f=)0.37 in 30% ethyl acetate/hexanes; ¹H-NMR(CDCl₃) δ 7.89-7.73 (m, 3H), 7.59 (bs, 1H), 7.50-7.41 (m, 3H), 7.32-7.15(m, 3H), 5.40 (dd, 1H, J=3.0, 6.3), 4.77 (t, 1H, J=7.4), 2.58 (ddd, 1H,J=2.8, 7.7, 13.8), 2.45 (ddd, 1 H, J=6.3, 7.2, 13.8), 2.14 (bs, 1H).

Trans-1-Methoxy-3-(2-naphthyl)indans, 10a and 10b

Sodium hydride (64.0 mg, 1.60 mmol) and methyl iodide (95.0 μL, 1.53mmol) were added to a solution of trans-3-(2-naphthyl)indan-1-ols 9a and9b (0.100 g, 0.384 mmol) at room temperature. The reaction was stirredunder a nitrogen atmosphere for 16 h. The reaction was quenched withexcess water (25 mL), then extracted with ether (3×25 mL). The combinedethereal phases were condensed to provide a yellow oil that solidifiedunder vacuum. The crude solid was purified by flash chromatography (12 gsilica, 10% ethyl acetate/hexanes) to afford the enantiomers 10a and 10bas a pale yellow oil (82 mg, 78%): R_(f=)0.47 in 10% ethylacetate/hexanes; ¹H-NMR (CDCl₃) δ 7.80-7.74 (m, 3H), 7.65 (bs, 1 H),7.51-7.41 (m, 3H), 7.30-7.17 (m, 3H), 7.01-6.98 (m, 1H), 4.92 (dd, 1H,J=1.7, 5.8), 4.76 (t, 1H, J=8.0), 3.43 (s, 3H), 2.70 (ddd, 1H, J=1.4,7.43, 13.76), 2.34 (ddd, 1H, J 6.05, 7.7, 13.76). Anal. (C₂₀H₁₈O)C, H.

Ethyl 3-(2-bromophenyl)-3-(3,4-dichlorophenyl)-2-cyanopropanoate, (3:3,4-Cl₂Ph)

Magnesium (0.30 g, 12.3 mmol) was added into a solution of1,2-dichloro-4-bromobenzene (2.76 g, 12.2 mmol) in ether (6 mL) and thereaction was stirred for 3 h. A solution of ethyl2-cyano-3-(2-bromophenyl)-2-propenoate (3 g, 9.15 mmol) in toluene (6mL) was added into the reaction mixture via an addition funnel over 15min. The reaction mixture was then heated to 90° C. and stirred for 45min. Ether was collected by Dean-Stark trap. The reaction mixture waspoured into ice containing conc. H₂SO₄ (1 mL). The H₂O layer wasextracted with ether (3×40 mL). Ether was removed on a rotary evaporatoraffording the crude product as a yellow oil (4.49 g, quantitative):R_(f) 0.32 (10% EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 7.57-7.63 (m, 7H), 5.24(dd, 1H, J=8, 8 Hz), 4.11-4.29 (m, 3H), 1.16 (ddd, 3H, J=7, 7, 14 Hz).

3-(2-Bromophenyl)-3-(3,4-dichlorophenyl)-propanoic acid, (4: 3,4-Cl₂Ph)

Ethyl 3-(2-bromophenyl)-3-(3,4-dichlorophenyl)-2-cyanopropanoate (4.49g, 9.45 mmol) in glacial acetic acid (20 mL), conc. H₂SO₄ (10 mL) andH₂O (10 mL) was refluxed at 100° C. for 24 h. The hot solution waspoured into ice in a beaker. White powder was formed and extracted withEtOAc (3×50 mL). Removal of solvent afforded 3.2 g of an oily solid. Theresidue was stirred in 3N NaOH (20 mL) for 30 min. The H₂O layer wasextracted with CHCl₃ (3×30 mL) to remove any organic side-products. TheH₂O layer was then acidified to pH 5 with 3N HCl (10 mL). White solidprecipitate was formed and collected by filtration through a sinteredfunnel. After drying in vacuo, the solid weighed 2.1 g (59%): ¹H-NMR(CDCl₃) δ 7.56 (dd, 1H, J=8, 1 Hz), 7.27-7.37 (m, 3H), 7.08-7.19 (m,3H), 4.96 (t, 1H, J=8 Hz), 2.95-3.11 (m, 2H).

3-(3,4-Dichlorophenyl)indanone, (5: 3,4-Cl₂Ph)

n-BuLi (2.5 M in hexanes, 4.15 mL, 10.4 mmol) was added dropwise over 15min into a solution of ethyl3-(2-bromophenyl)-3-(3,4-dichlorophenyl)-propanoic acid (1.77 g, 4.73mmol) in ether (23 mL) at −10° C. After the addition, the reaction wasallowed to stir at 0° C. in an ice bath for 40 min. 3N HCl (3 mL) wasadded slowly followed by H₂O (5 mL). The H₂O layer was extracted withether (3×30 mL). The solvent was removed on a rotary evaporator. Theresidue was purified by flash chromatography (20% EtOAc/hexanes) to givea white solid (0.6 g, 46%): mp 112-113° C.; R_(f) 0.39 (20%EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 7.82 (d, 1H, J=8 Hz), 7.60 (ddd, 1H,J=8, 8, 1 Hz), 7.42-7.48 (m, 1H), 7.37 (d, 1H, J=8 Hz), 7.24-7.27 (m,1H), 7.22 (d, 1H, J=2 Hz), 6.94 (dd, 1H, J=8, 2 Hz), 4.54 (q, 1H, J=4Hz), 3.23 (dd, 1H, J=19, 8 Hz), 2.61 (dd, 1H, J=19, 4 Hz). Anal.(C₁₅H₁₀Cl₂₀) C, H, Cl.

Cis-3-(3,4-Dichlorophenyl)indan-1-ol, (6: 3,4-Cl₂Ph

K-Selectride (1M in THF, 2.7 mL) was added dropwise into a solution of3-(3,4-dichlorophenyl)indanone (0.36 g, 1.28 mmol) at 0° C. The reactionwas allowed to stir at 0° C. for 3 h. 3M NaOH (0.5 mL) was added slowlyfollowed by the addition of 30% H₂O₂ (0.5 mL). Water (20 mL) was addedand the water layer was extracted with ether (3×20 mL). Ether wasremoved on a rotary evaporator. The residue was purified by flashchromatography to give 0.32 g (88%) of 6 as a colorless oil: R_(f) 0.43(EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 7.48 (d, 1H, J=7 Hz), 7.38 (d, 1H, J=8Hz), 7.32-7.35 (m, 1H), 7.29-7.30 (m, 1H), 7.24-7.26 (m, 1H), 7.07 (dd,1H, J=8, 2 Hz), 6.94 (d, 1H, J=8 Hz), 5.29 (q, 1H, J=7 Hz), 4.15 (t, 1H,J=8 Hz), 3.01 (qd, 1H, J=7, 8 Hz), 2.06 (d, 1H, J=7 Hz), 1.88 (qd, 1H,J=7, 9 Hz). Anal. (C₁₅H₁₂OCl₂) C, H, Cl.

Cis-1-Methoxy-3-(3,4-dichlorophenyl)indans, (7: 3,4-Cl₂Ph)

Sodium hydride (60% dispersion, 10 mg, 0.251 mol) was added into asolution of methyl iodide (16 mg, 0.25 mmol) andcis-3-(3,4-dichlorophenyl)indan-1-ol (35 mg, 0.125 mmol) in THF (1 mL).The mixture was stirred for 4 h. 3N HCl (1 mL) and H₂O (5 mL) were addedand the water layer was extracted with ether (3×10 mL). Ether wasremoved on a rotary evaporator. The residue was purified by flashchromatography (10% EtOAc/hexanes) to afford 18 mg (49%) of 7 as acolorless oil: R_(f) 0.71 (20% EtOAc/hexanes); ¹H-NMR (CDCl₃) δ7.46-7.49 (m, 1H), 7.23-7.38 (m, 4H), 7.07 (dd, 1H, J=8, 2 Hz),6.93-6.96 (m, 1H), 4.90 (t, 1H, J=6 Hz), 4.17 (t, 1H, J=8 Hz), 2.94 (qd,1H, J=7, 6 Hz), 1.96 (qd, 1H, J=7, 6 Hz). Anal. (C₁₆H₁₄OCl₂) C, H.

Benzoic acid 3-phenylindan-1-yl ester. (8: 3,4-Cl₂Ph)

Cis-3-(3,4-Dichlorophenyl)indan-1-ol (50 mg, 0.18 mmol),triphenylphosphine (0.100 g, 0.376 mmol), diethyl azodicarboxylate (0.06mL, 0.358 mmol) and benzoic acid (44 mg, 0.358 mmol) in THF were stirredovernight. The organic solvent was removed on a rotary evaporator. Theresidue was purified by flash chromatography (10% EtOAc/hexanes) toafford 50 mg (73%) of 8 as a colorless oil: R_(f) 0.63 (20%EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 8.02-8.05 (m, 2H), 7.51-7.63 (m, 2H),7.25-7.47 (m, 6H), 7.00-7.05 (m, 1H), 6.55 (dd, 1H, J=6, 2 Hz), 4.66 (t,1H, J=8 Hz), 2.78 (qd, 1H, J=7, 2 Hz), 2.47 (qd, 1H, J=7, 7 Hz).

Trans-3-(3,4-Dichlorophenyl)indan-1-ol, (9: 3,4-Cl₂Ph)

Potassium hydroxide (3M, 1 mL) was added into a solution of benzoic acid3-phenyl-indan-1-yl ester (50 mg, 0.131 mmol) in methanol (2 mL) and THF(2 mL). The reaction mixture was stirred for 2 h. 3M HCl (0.5 mL) wasadded dropwise until pH=3.0, followed by the addition of H₂O (5 mL). TheH₂O layer was extracted with ether (3×20 mL) to afford an oil (47 mg)R_(f) 0.63 (20% EtOAc/hexanes). The crude oil was used in the next stepwithout further purification.

Trans-1-Methoxy-3-(3,4-dichlorophenyl)indans, (10:3,4-Cl₂Ph)

Sodium hydride (60% dispersion, 26 mg, 0.674 mmol) was added into asolution of trans-3-(3,4-dichlorophenyl)indan-1-ol (47 mg, 0.168 mmol)and CH₃I (42 L, 0.674 mmol) in THF (2 mL). The reaction mixture wasstirred overnight. H₂O (5 mL) was added and the H₂O layer was extractedwith ether (3×20 mL). The organic solvent was removed on a rotaryevaporator. The residue was purified by flash chromatography (10%EtOAc/hexanes) to afford 20 mg (50%) of a colorless oil: R_(f) 0.50 (10%EtOAc/hexanes); ¹H-NMR (CDCl₃) δ 7.44-7.48 (m, 1H), 7.36 (d, 1H, J=8Hz), 7.25-7.32 (m, 2H), 7.23 (d, 1H, J=2 Hz), 6.96-7.00 (m, 2H), 4.87(dd, 1H, J=6, 2 Hz), 4.55 (t, 1H, J=8 Hz), 3.41 (s, 3H), 2.65 (td, 1H,J=7, 2 Hz), 2.18 (qd, 1H, J=7, 8 Hz). Anal. (C₁₆H₁₄OCl₂) C, H, Cl.II. Synthesis of Tetrahydropyranyl Esters

2-ARYL TETRAHYDROPYRAN-2-YL ACETIC ACID METHYL ESTERS (FOUR ENANTIOMERS)

In general, synthesis of the 2-aryl substituted tetrahydropyran-2-ylacetic acid methyl esters can be accomplished via an identical route tothat presented below for the 2-(3,4-dichlorophenyl) analogs.

2-Chlorotetrahyropyran, prepared by passing hydrogen chloride gas into asolution of 2,3-dihydrotetrahydropyran in ether [Ficini, J. Bull. Soc.Chim. Fr. 119-124 (1956)], was reacted with the enolate of theappropriate methyl arylacetates to provide the desired product,exemplified below as a mixture of 1 and 2, in 77% yield (see Scheme 1 inFIG. 2).

The product possesses two chiral centers (2,2′) and consequently thereis a pair of enantiomers for each diastereomer. Therefore there existfour isomers as shown in Scheme 2 in FIG. 3 (Compounds 1 and 2).

The product mixture (1 and 2) obtained from the reaction of2-chlorotetrahyropyran with the enolate of methyl3,4-dichlorophenylacetate presented as two spots on TLC in a ratio of1.0:1.4 (¹H-NMR). These two spots represent the two diastereomeric pairsof enantiomers 1 (1a and 1b) and 2 (2a and 2b).

The two diastereomers 1 and 2 were separated by column chromatography toobtain diastereomer 1 as an oil (2S,2′R and 2R,2′S) and diastereomer 2as a solid (2S,2′S and 2R,2′R). (The assignment of chirality wasachieved by X-ray crystallographic analysis, see later). These pairs ofmethyl esters 1 and 2 were then hydrolyzed to their acids 4 and 3respectively. To avoid epimerization, a neutral reagent, trimethylsilyliodide (TMS-I), was used (W. P. Weber, Silicon Reagents for OrganicSynthesis, Springer-Verlag, Berlin, Heidelberg, N.Y., 1983, page 30-31).

The enantiomeric acid pair (3a and 3b: S,S- and R,R-) resulting fromhydrolysis of 2 was then transformed (Scheme 3 in FIG. 4) intodiastereomeric menthyl esters (5a and 5b) by treatment of their acidchlorides with optically pure L-menthol. Careful column chromatographythen allowed separation of the two newly formed diastereomeric menthylesters 5a and 5b. These two diastereomerically pure menthyl esters wereeach separately hydrolyzed (TMS-1) to give the two optically pure acids3a and 3b.

One of the acids (3a) was crystallized and its absolute configurationwas determined by X-ray crystallography. Thus the configuration of 3awas proved to be 2S,2′S. Therefore 3b was proved to be the 2R,2′Renantiomer.

Acids 3a and 3b were then methylated with trimethylsilyl diazomethane tofurnish optically pure target molecules 2a-(2S,2′S) (O-1794) and2b-(2R,2′R) (O-1783).

In contrast, the menthol esters of the diastereomeric pair of acids 4aand 4b proved difficult to separate by column chromatography.

Therefore to obtain the remaining two isomers 1a-(2S,2′R) and1b-(2R,2′S), the racemic acids (as a mixture of 4a and 4b) fromhydrolysis of the mixed methyl esters [1a-(2S,2′R) and 1b-(2R,2′S)] wereconverted (Scheme 4) to the diastereomeric indanyl esters (6a and 6b) byreaction of their acid chlorides with (S)-(+)-1-indanol. The two indanylesters were resolved by medium pressure flash column chromatography(ΔR_(f)<0.02). They were then each separately hydrolyzed withtrimethylsilyl iodide to provide the two optically pure acids 4a and 4band methylated with trimethylsilyl diazomethane to furnish theenantiomerically pure methyl esters 1a-(2S,2′R) and 1b-(2R,2′S).

One of the optically pure acids thus obtained (4b) was reacted, via itsacid chloride, with p-nitrophenol to obtain the p-nitrophenylester. Thiscompound was then recrystallized and X-ray crystallographic analysis ofthis p-nitrophenylester derivative then confirmed its configuration as2R,2′S. Therefore the methyl ester derived from acid 4b is compound1b-(2R,2′S) (0-1792). Therefore the remaining enantiomer is 1a-(2S,2′R)(0-1793) (FIG. 5).

The diastereomeric mixture of the 2-naphthyl analogs of 1 and 2 wereprepared by a similar route (Scheme 1, FIG. 2). Their binding to the DATand SERT was as follows DAT: IC₅₀=0.3μM; SERT IC₅₀=5 μM. The sameexchange was conducted in the methylphenidate series. Therefore,carbocyclic analogs of methylphenidate were prepared. Reaction of eithercyclohexyl bromide or cyclopentyl bromide with methyl3,4-dichlorophenylacetate resulted in complex mixtures. In contrast,reaction with the nitrile (Scheme 5, FIG. 6) provided the desiredproducts, which could be hydrolyzed and re-esterified to provide thecarba analogs. Thus commercially available 7 was reacted with cyclohexylbromide to provide 8 (or with cyclopentyl bromide to provide 10).Hydrolysis and reesterification then gave 9 and 11 respectively. TABLE 1Summary of Binding Data: Inhibition of [³H]WIN 35,428 binding to thedopamine transporter and [³H]citalopram binding to the serotonintransporter in rhesus (macaca mulatta) or cynomolgus monkey (macacafascicularis) caudate-putamen. Compound Number DAT IC₅₀ (nM) SERT IC₅₀(nM) O-1793 1a-(2S,2′R) 736 ± 59   >10,000 l-erythro O-1792 1b-(2R,2′S)193 ± 3.5  >10,000 d-erythro O-1794 2a-(2S,2′S) 34 ± 8.6 1,655 ± 317l-threo O-1783 2b-(2R,2′R) 17 ± 1.3 >10,000 d-threo Naphthyl mixture 3005,000  8 127 8,000  9 146 12,000 10 128 10,000 11 47 7,000Each value is the mean of 3 or more independent experiments eachconducted in different brains and in triplicate. Errors generally do notexceed 15% between replicate experiments. Highest doses tested weregenerally 10-100 μM.“DAT” = Inhibition of WIN 35,428 binding to the dopamine transporter;“SERT” = Inhibition of citalopram binding to the serotonin transporter

Table of Data for Four Enantiomeric Acids

Number 4a 4b 3a 3b Configuration 2S,2′R 2R,2′S 2S,2′S 2R,2′R Meltingpoint ° C. 124.2- 124.1- 138.9- 139.1- 125.2 125.1 139.9 140 [I]_(D) ²⁰(c = 1, CHCl₃) +14.0° −13.9° +18.8° −19.1°

EXPERIMENTAL SECTION

NMR spectra were recorded in CDCl₃ on a JEOL 300 NMR spectrometeroperating at 300.53 MHz for ¹H, and 75.58 MHz for ¹³C. TMS was used asinternal standard. Melting points are uncorrected and were measured on aGallenkamp melting point apparatus. Thin layer chromatography (TLC) wascarried out on Baker Si250F plates. Visualization was accomplished witheither UV exposure or treatment with phosphomolybdic acid (PMA). Flashchromatography was carried out on Baker Silica Gel 40 mM. Elementalanalyses were performed by Atlantic Microlab, Atlanta, Ga. All reactionswere conducted under an inert (N2) atmosphere. Optical rotations weremeasured on a Perkin Elmer 241 Polarimeter. All reactions were conductedunder an inert (N2) atmosphere. [³H]WIN 35,428(2β-carbomethoxy-3β-(4-fluorophenyl)-N-[³H]methyltropane, 79.4-87.0Ci/mmol) and [³H]citalopram (86.8 Ci/mmol) were purchased fromDuPont-New England Nuclear (Boston, Mass.). A Beckman 1801 scintillationcounter was used for scintillation spectrometry. Bovine serum albumin(0.1%) was purchased from Sigma Chemicals. (R)-(−)-Cocaine hydrochloridefor the pharmacological studies was donated by the National Institute onDrug Abuse [NIDA]. Room temperature is ca. 22° C. TMSI: trimethylsilyliodide. Yields have not been optimized.

2-Chlorotetrahydropyran.

Dry HCl gas was bubbled through a solution of 3,4-dihydro-2H-pyran (34.1g, 0.41 mol) in 150 mL of anhydrous ether cooled in a dry-ice/acetonebath for ca. 2 h. Ether was removed by evaporation and fractionaldistillation of the residue under reduced pressure (bp 36-39° C./18Torr) furnished 36.75 g (0.31 mol, 75%) of colorless oil. ¹H-NMR (CDCl₃)δ 1.4-1.8 (m, 3H), 1.9-2.2 (m, 3H), 3.7-3.8(m, 1H), 3.9-4.1 (m, 1H),6.27 (t, J=0.54 Hz, 1H). This compound was used immediately in the nextstep.

2-(3,4-Dichlorophenyl)tetrahydropyran-2-yl acetic acid methyl esters, 1and 2.

n-Butyl lithium (Aldrich, 2.5 M in hexane) (20.8 mL, 52 mmol) was addeddropwise to a solution of diisopropylamine (4.8 g, 48 mmol) in anhydrousdiethyl ether (100 mL). After stirring at 0° C. for 1.5 h (yellowsolution), methyl 3,4-dichlorophenylacetate (9.6 g, 44 mmol) in THF (20mL) was added dropwise over 30 min; the solution became black. Aftercompletion of addition, the solution was stirred for a further 2 h. Theround-bottom flask was then immersed in a dry-ice-acetone bath (−78° C.)and the mixture stirred for an additional 20 min.

The mixture was then added dropwise to a solution of2-chlorotetrahydropyran (5.3 g, 44 mmol) in 40 mL of THF over 1 h andthen slowly warmed to room temperature and stirred overnight. Cold (0°C.) 0.5 N hydrochloric acid (104 mL) was added, followed by 400 mL ofethyl acetate. The layers were separated and the organic layer waswashed with brine and dried over anhydrous sodium sulfate.

TLC showed two major spots, both of which were UV and PMA active in aratio of 1:1.4 based on ¹H-NMR.

The crude product was purified by column chromatography using gradientethyl acetate in hexane (5-15% of ethyl acetate). Total yield was 54%.The first products 1 were obtained as an oil (2.97 g): R_(f=)0.59 (20%ethyl acetate in hexane); ¹H-NMR (CDCl₃) δ 7.47 (d, J=2.2 Hz, 1H), 7.38(d, 8.5 Hz, 1H), 7.21 (dd, J=2.2, 8.5 Hz, 1H), 3.93-3.80 (m, 2H), 3.67(s, 3H), 3.55 (d, J=11.5 Hz, 1H), 3.40-3.26 (m, 1H), 1.90-1.20 (m, 6H).¹³C-NMR 171.74, 136.61, 132.37, 131.56, 130.97, 130.26, 128.49, 78.22,68.95, 56.94, 52.33, 31.67, 29.97, 25.72, 23.24. The second products 2were obtained as a solid (4.27 g): R_(f=)0.50 (20% ethyl acetate inhexane); mp 65° C.; ¹H-NMR (CDCl₃) δ 7.47 (d, J=1.9 Hz, 1H), 7.38 (d,J=8.3 Hz, 1H), 7.19 (dd, J=1.9, 8.3 Hz, 1H), 3.99 (dt); ¹³C-NMR 172.69,135.45, 132.83, 132.07, 130.63, 128.18, 79.24, 68.91, 57.41, 52.36,29.16, 25.72, 23.13.

2-(3,4-Dichlorophenyl)tetrahydropyran-2-yl acetic acids, 3a and 3b

The combined methyl esters 2 (8.5 g, 28 mmol) were dissolved inanhydrous chloroform (10 mL) at room temperature. Trimethylsilyl iodide(14 g, 70 mmol, 2.5 equiv.) was added dropwise with stirring. Themixture was heated at 80° C. overnight. It was then cooled to roomtemperature and the volatiles were evaporated. Aqueous sodiumthiosulfate solution (1%) and 25 mL of diethyl ether were added to theresidue and the two layers were separated. The colorless ether phase wasdried over sodium sulfate, filtered, and concentrated. The residue waspurified by column chromatography (30% ethyl acetate in hexane, then 50%ethyl acetate in hexane). The acids 3a and 3b were obtained (5.2 g, 65%combined yield). ¹H-NMR (CDCl₃) δ 7.43 (d, J=2.2 Hz, 1H), 7.40 (d, J=8.5Hz, 1H), 7.21 (dd, J=8.3, 2.2 Hz, 1H), 3.98 (dd, J=10.8, 2.3 Hz, 1H),3.87 (m, 1H), 3.61 (d, J=7.4 Hz, 1H), 3.4 (m, 1H), 1.95-1.20 (m, 6H).

2-(3,4-Dichlorophenyl)tetrahydropyran-2-yl acetic acid menthyl esters,5a and 5b

The combined 3,4-dichlorophenyl tetrahydropyran-2-yl acetic acids 3a and3b (0.86 g, 3.0 mmol) were dissolved in 80 mL of anhydrousdichloromethane. Three drops of DMF were added, followed by the dropwiseaddition of oxalyl chloride (0.58 g, 4.8 mmol, 1.6 equiv.) at roomtemperature. The solution was stirred for 3 h. Volatiles were removedand anhydrous THF (75 mL) was introduced followed by the addition ofpyridine (0.5 g). L-Menthol (0.47 g, 3.0 mmol) in THF (5 mL) was addeddropwise. The reaction mixture was stirred overnight and then pouredinto 100 mL of water. Ether (150 mL) was added. The layers wereseparated and the aqueous phase was further extracted with ether. Thecombined organic phase was washed with brine and dried over sodiumsulfate, filtered and concentrated.

TLC (10% ethyl acetate in hexane) showed two major spots (R_(f) 0.54 and0.50). After column chromatography (hexane 800 mL, 1% ethyl acetate inhexane 800 mL, and finally 3% ethyl acetate 800 mL), 400 mg of the firstproduct 5a: R_(f=)0.54 (10% ethyl acetate/hexanes); ¹H-NMR (CDCl₃) 7.50(d, J=2.19 Hz, 1H), 7.38 (d, J=8.25 Hz, 1H), 7.22 (dd, J=2.19, 8.25 Hz,1H), 4.70 (td, J=4.38, 11.04 Hz, 1H), 3.94 (dt, J=2.19, 11.28 Hz, 1H),3.79 (td, J=2.19, 10.44 Hz, 1H), 3.45 (td, J=2.73, 9.06 Hz, 1H), 3.46(d, J=9,87 Hz, 1H), 2.0-0.9 (m, 15H), 0.88 (d, J=7.68 Hz, 3H), 0.86 (d,J=6.6 Hz, 3H), 0.72 (d, J=6.87 Hz, 3H); ¹³C-NMR (CDCl₃) 171.76, 135.69,132.55, 131.70, 130.55, 130.37, 120.21, 79.39, 74.93, 68, 53, 57.83,47.03, 40, 53, 34.20, 31.37, 28.96, 25.70, 23.07, 21.96, 20.86, 15.86;and 425 mg of a second product 5b was obtained (65% combined yield):R_(f=)0.50 (10% ethyl acetate/hexanes); ¹H-NMR (CDCl₃) 7.47 (d, J=2.19Hz, 1H), 7.38 (d, J=8.22 Hz, 1H), 7.20 (dd, J=2.19, 8.22 Hz, 1H), 4.68(td, J=4.41, 10.98 Hz, 1H), 3.94 (dt, J=2.19, 11.25 Hz, 1H), 3.83 (td,J=2.19, 10.17 Hz, 1H), 3.44 (td, J=3.03, 12.10 Hz, 1H), 3.45 (d, J=9.90Hz, 1H), 2.0-0.9 (m, 15H), 0.88 (d, J=6.66 Hz, 3H), 0.78 (d, J=6.87 Hz,3H), 0.61 (d, J=6.87 Hz, 3H); ¹³C-NMR (CDCl₃) 171.15, 135.76, 132.56,131.72, 130.52, 130.42, 128.08, 78.86, 75.03, 68, 61, 58.27, 47.15, 40,72, 34.21, 31.40, 29.02, 25.79, 25.62, 23.23, 23.07, 21.96, 20.67,15.91.

2-(3,4-Dichlorophenyl)tetrahydropyran-2-yl acetic acid, 4a and 4b

The methyl ester 1 (4.4 g, 14.5 mmol) was dissolved in anhydrouschloroform (60 mL) and Me₃SiI (10.0 g) was added. The mixture was heatedin an oil bath at 80° C. After 20 h, ¹H-NMR showed the reaction was only25% complete. The reaction mixture was then heated for an additional 4days whereupon it was cooled to room temperature and ice (20 g) wasadded, followed by addition of Na₂SO₃ solution (0.5N) to the point thatalmost no red color remained. The layers were separated and the aqueousphase was extracted with CH₂Cl₂ (80 mL×2). The combined organic extractswere dried over Na₂SO₄. The crude product was purified by columnchromatography (200 g of silica gel, CH₂Cl₂, 3L, 3% MeOH in CH₂Cl₂, 3L)and 3.4 g of pure product, 4a and 4b, was obtained (83% yield). ¹H-NMR(CDCl₃) δ7.47 (d, J=2.19 Hz, 1H), 7.40 (d, J=8.52 Hz, 1H), 7.21 (dd,J=8.52, 2.19 Hz, 1H), 3.97 (dd, J=10.71, 2.22 Hz, 1H), 3.60 (d, J=7.14Hz, 1H), 3.45-3.36 (m, 1H), 1.90-1.20 (m, 6H).

2-(3,4-Dichlorophenyl)tetrahydropyran-2-yl acetic acid indanyl esters,6a and 6b

The enantiomeric pair of 2-(3,4-dichlorophenyl) tetrahydropyran-2-ylacetic acids 4a and 4b (4.0 g, 13.83 mmol) was dissolved in anhydrousCH₂Cl₂ (80 mL) and 4 drops of DMF were added. Oxalyl chloride (3.5 g,27.7 mmol, 2 equiv.) was added dropwise while the solution wasvigorously stirred. Evolution of bubbles was observed. After completionof addition, the light yellow solution was stirred at room temperaturefor a further 2.5 h.

Solvent was removed by evaporation and the residue was dried in vacuo.(S)-(+)-1-Indanol (1.87 g, 13.9 mmol) was dissolved in anhydrous THF (25mL) and dry pyridine (25 mL) and cooled to 0° C. The acid chloride,prepared as above, in THF (50 mL) was added dropwise to this cold,stirred solution and stirred at 0° C. for 2 h, and then warmed up toroom temperature and stirred overnight. ¹H-NMR data show that the ratioof 6a (R_(f)0.71 in 10% EtOAc, 90% hexane, developed 3 times) to 6b(R_(f)0.67) was 4:5 based on the peaks at 3.53 ppm and 3.54 ppm. Themixture was evaporated to remove most of the solvent. The residue wasredissolved in a mixture of hexane/ethyl acetate (10:5) (80 mL) toprovide a light yellow suspension. The mixture was loaded on a shortsilica gel pad and washed with hexane/ethyl acetate (10:1). The productfractions were combined and evaporated and dried. A light yellow oil wasobtained (4.0 g, 71.4% crude yield). It was purified by columnchromatography (300 g of silica gel, 0.4% of ethyl acetate, 99.6% ofhexane, 4L, then 0.8% ethyl acetate in hexane, 5L). A total of 0.6 g of6a, 1.0 g of a mixture of 6a and 6b, and 0.5 g of 6b were obtained.¹H-NMR (CDCl₃) 6a: δ 7.49 (d, J=2.19 Hz, 1H), 7.39-7.10 (m, 6H), 6.20(m, 1H), 3.92-3.80 (m, 2H), 3.53 (d, J=8.79 Hz, 1H), 3.34-3.25 (m, 1H),3.1-3.0 (m, 1H), 2.9-2.8 (m, 1H), 2.5-2.4 (m, 1H), 2.0-1.1 (m, 6H).¹³C-NMR 171.07, 144.31, 140.56, 136.56, 132.19, 131.39, 130.90, 130.08,129.04, 128.50, 126.73, 125.34, 124.85, 79.09, 78.16, 68.80, 57.08,31.99, 30.13, 29.81.

6b: ¹H-NMR (CDCl₃) 7.47 (d, J=2.19 Hz, 1H), 7.37 (d, J=8.25 Hz, 1H),7.31-7.18 (m, 5H), 6.17 (m, 1H), 3.92-3.80 (m, 2H), 5.53 (d, J=8.52 Hz,1H), 3.40-3.27 (m, 1H), 3.14-3.03 (m, 1H), 2.95-2.82 (m, 1H), 2.59-2.40(m, 1H), 2.2-1.2 (m, 6H). ¹³C-NMR 171.09, 144.28, 140.37, 136.48,132.16, 131.37, 130.95, 130.07, 129.05, 128.51, 126.72, 125.28, 124.82,79.18, 78.16, 68.84, 57.04, 32.23, 30.15, 29.81, 25.61, 23.14.

Hydrolysis of menthyl (5a and 5b) and indanyl (6a and 6b) esters(General Procedure)

The hydrolyses of the menthyl and indanyl esters to the correspondingacids was conducted similarly and yields were in a range of 38-55%. Theprocedure is exemplified for 6a below.

2S-(3,4-Dichlorophenyl)tetrahydropyran-2′R-yl acetic acid, 4a-2S,2′R.

The indanyl ester 6a (1.65 g, 4.07 mmol) was dissolved in anhydrouscarbon tetrachloride (25 mL). Trimethylsilyl iodide (2.4 g, 12 mmol, 3equiv.) was added. The mixture was heated at 90° C. with stirring for 18h.

The reaction mixture was cooled to 0° C., cold water (20 mL) anddichloromethane (50 mL) were added and layers were separated. Theaqueous phase was washed with dichloromethane (50 mL×2). The combinedorganic phases were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated to dryness. The residue was purified bycolumn chromatography (10% methanol in dichloromethane) and 600 mg ofproduct 4a was obtained (55% yield). Mp 124.2-125.2° C. [α]_(D) ²⁰=14.0°(c=1, CHCl₃); ¹H-NMR (CDCl₃) δ7.47 (d, J=2.19 Hz, 1H), 7.40 (d, J=8.52Hz, 1H), 7.21 (dd, J=8.52, 2.19 Hz, 1H), 3.97 (dd, J=10.77, 2.22 Hz,1H), 3.92-3.83 (m, 1H), 3.60 (d, J=7.14 Hz, 1H), 3.45-3.36 (m, 1H),1.9-1.2 (m, 6H),

2R-(3,4-Dichlorophenyl)tetrahydropyran-2′S-yl acetic acid, 4b-2R,2′S.

Acid 4b was obtained from 6b as described above for 4a. ¹H-NMR data areidentical 4a. Mp 124.1-125.1° C.[α]_(D) ²⁰=−13.9° (c=1, CHCl₃). ¹³C-NMR(CDCl₃) 176.67, 135.53, 132.36, 131,80, 131.18, 130.21, 128.74, 77.82,68.95, 56.60, 29.56, 25.49, 23.04

2S-(3,4-Dichlorophenyl)tetrahydropyran-2′S-yl acetic acid, 3a-2S,2′S.

Acid 3a was obtained from 5a as described for 4a above. M.p.138.9-139.9° C. [α]_(D) ²⁰=18.8° (c=1, CHCl₃). ¹H-NMR (CDCl₃) δ7.45 (d,J=1.95 Hz, 1H), 7.40 (d, J=8.25 Hz, 1H), 7.18 (dd, J=8.25, 2.22 Hz, 1H),4.06 (dt, J=11.22, 1.92 Hz, 1H), 3.9-3.7 (m, 1H), 3.52 (d, J=9.33 Hz,1H), 3.50 (td, J=11.25, 3.3 Hz, 1H), 1.9-1.1 (m, 6H).

2R-(3,4-Dichlorophenyl)tetrahydropyran-2′R-yl acetic acid, 3b-2R,2′R.

Acid 3b was obtained from 5b as described for 4a above. NMR data areidentical to acid 3a. Mp 139.1-140.1° C. [α]_(D) ²⁰=−19.1° (c=1, CHCl₃)

2-(3,4-Dichlorophenyl)tetrahydropyran-2-yl acetic acid methyl esters,1a, 1b, 2a, 2b (General Procedure)

Acids 3a, 3b, 4a, 4b, were methylated with trimethylsilyl diazomethaneto obtain the methyl esters. The following procedure is representative.

2S-(3,4-Dichlorophenyl)tetrahydropyran-2′R-yl acetic acid methyl ester,1a-2S, 2′R.

Acid 4a-2S, 2′R (90 mg, 0.31 mmol) was dissolved in anhydrous toluene (4mL) and anhydrous methanol (1 mL). Trimethylsilyl diazomethane (0.63 mL,2.0M in hexane, 1.25 mmol, 4 equiv) was slowly added while stirring atroom temperature and the mixture was stirred for 5 h. Volatiles wereremoved in vacuo. The residue (100 mg) was purified by columnchromatography (2% ethyl acetate in hexane) to provide 1a-2S, 2′R as anof oil (61 mg, 64% yield). ¹H-NMR (CDCl₃) δ7.47 (d, J=2.19 Hz, 1H), 7.39(d, J=8.25 Hz, 1H), 7.22 (dd, J=8.25, 2.19 Hz, 1H), 3.92-3.81 (m, 1H),3.68 (s, 3H), 3.56 (d, J=8.52 Hz, 1H), 3.39-3.20 (m, 1H), 1.9-1.1 (m,6H). Anal. calcd. for C₁₄H16O₃Cl₂═C 55.46, H 5.32, Cl 23.39; found: C55.56, H 5.42, Cl 23.51.

2R-(3,4-Dichlorophenyl)tetrahydropyran-2′S-yl acetic acid methyl ester,1b-2R, 2′S.

Methyl ester 1b was prepared from 4b as described above for 1a. ¹H-NMRdata identical to those of 1a. Anal. calcd. for C₁₄H₁₆O₃Cl₂: C 55.46, H5.32, Cl 23.39; found: C 55.55, H 5.38, Cl 23.51.

2S-(3,4-Dichlorophenyl)tetrahydropyran-2′S-yl acetic acid methyl ester,2a-2S, 2′S.

Methyl ester 2a was prepared from 3a as described above for 1a. ¹H-NMR(CDCl₃) δ 7.48 (d, J=1.92 Hz, 1H), 7.39 (d, J=8.25 Hz, 1H), 7.25 (dd,J=8.25, 2.19 Hz, 1H), 4.03-3.95 (m, 1H), 3.84 (td, J=10.71, 2.19 Hz,1H), 3.70 (s, 3H), 3.50 (d, J=9.9 Hz, 1H), 3.47 (td, J=11.34, 3.3 Hz,1H), 1.9-1.0 (m, 6H). Anal. calcd. for C₁₄H₁₆O₃Cl₂: C 55.46, H 5.32, Cl23.39; found: C 55.63, H 5.43, Cl 23.47,

2R-(3,4-Dichlorophenyl)tetrahydropyran-2′R-yl) acetic acid methyl ester,2b-2R, 2′R.

Methyl ester 2b was prepared from 3b as described above for 1a. ¹H-NMRdata are identical to those of 2a. Anal. calcd. for C₁₄H₁₆O₃Cl₂: C55.46, H 5.32, Cl 23.39, found: C 55.53, H 5.38, Cl 23.27.

2R-(3,4-Dichlorophenyl)tetrahydro ran-2′S-yl acetic acid p-nitrophenylester, (P-Nitrophenyl ester of 4b-2R,2′S).

Compound 4b-(2R,2′S) obtained from 1b-(2R,2S′) (100 mg) was dissolved inanhydrous dichloromethane (5 mL). One drop of DMF was added. Oxalylchloride (0.14 g) was slowly added and the reaction mixture was stirredat room temperature for 3 h. Solvent was then removed by evaporation.

4-Nitrophenol (56 mg) was dissolved in anhydrous THF (3 mL) and pyridine(85 mg) was added. The mixture was cooled to 0° C. in an ice-water bath.To this cooled, stirred solution was added the acid chloride preparedabove in 2 mL of THF over 10 min. The mixture was warmed up to roomtemperature and stirred overnight. The crude product was purified bycolumn chromatography (0.6% ethyl acetate in hexane). The product (0.105g) was obtained as a gummy material (75% yield). R_(f)=0.46 (20% ethylacetate in hexane). ¹H-NMR (CDCl₃) δ 8.3-8.2 (m, 2H), 7.55 (d, J=2.19Hz, 1H), 7.45 (d, J=8.25 Hz, 1H), 7.32-7.18 (m, 3H), 4.07-3.91 (m, 2H),3.83 (d, J=7.41 Hz, 1H), 3.46-3.37 (m, 1H), 2.0-1.2 (m, 6H). The gum wasrecrystallized from pentane. X-ray structural analysis showed theenantiomerically pure p-nitrophenyl ester of 4b to be of 2R,2′Sconfiguration.

2,2-(3,4-dichlorophenyl)cycloalkyl acetic acid methyl ester.

The following procedure is representative. To a stirred solution oft-BuOK (11.0 mL, 1.0 M in THF), a solution of 3,4-dichlorophenylacetonitrile (1.86 g, 10.0 mmol) in THF (20 mL) was slowly added. Themixture was stirred for 0.5 h, and cyclopentyl bromide (1.57 g, 10.5mmol) in THF (10 mL) was added. The dark brown solution was stirred at22° C. for 1 h and then heated to reflux overnight. After cooling it wastransferred to a separatory funnel and EtOAc (200 mL) and water (150 mL)were added. The organic phase was separated and washed consecutivelywith H₂O and brine, dried (Na₂SO₄), concentrated and purified by columnchromatography (1-2% EtOAc in hexane) to yield 10 (α-cyclopentyl-3,4-dichlorobenzylcyanide) as an oil (1.78 g; 70%). ¹H NMR δ 7.45 (d, 1H),7.43 (d, 1H), 7.18 (dd, 1H), 3.69 (d, J=7.7 Hz, 1H), 2.4-1.2 (m, 9H).Anal. (C₁₃H₁₃NCl₂) C, H, Cl.

The nitrile 10 (α-cyclopentyl-3,4-dichlorobenzylcyanide) (1.2 g, 4.7mmol) was dissolved in HCl-methanol solution (65 mL, 10.3 M), sealedwith a stopper and stirred at 22° C. for 2 days. 6N Hydrochloric acid(30 mL) was slowly added to the mixture which was stirred for 10 min andevaporated to dryness. A further 50 mL of HCl-methanol solution (10.3 M)was added and stirring continued for 4 days. An additional 30 mL of 6Nhydrochloric acid was added and the mixture brought to reflux for 2days. After cooling, EtOAc (200 mL) and water (150 mL) were added. Theorganic phase was washed with water, followed by brine, dried (Na₂SO₄)and concentrated. The oil obtained (R_(f) 0.45, 10% EtOAc in hexane,)was purified by column chromatography (0.5%-1% EtOAc in hexane) toprovide α-cyclopentyl-3,4-dichlorobenzylcyanide andα-cyclopentyl-3,4-dichlorophenylcyclohexyl acetic acid methyl ester (11)as a colorless oil (1.1 g, 82%). ¹H NMR δ 7.45 (d, 1H), 7.35 (d, 1H),7.19 (dd, 1H), 3.66 (s, 3H), 3.23 (d, J=11.3 Hz, 1H), 2.6-2.4, m, 1H),2.0-1.8 (m, 1H), 1.8-0.8 (m, 7H). Anal. (C₁₄H₁₆O₂Cl₂) C, H, Cl.

α-cyclohexyl-3,4-dichlorobenzylcyanide (8).

(46%), ¹H NMR δ 7.45 (d, 1H), 7.39 (d, 1H), 7.42 (dd, 1H), 3.60 (d,J=6.3 Hz, 1H), 1.9-1.1 (m, 11H). Anal. (C₁₄H₁₅NCl₂) C, H, Cl.

α-cyclohexyl-3,4-dichlorophenylcyclohexyl acetic acid methyl ester (9).

(40%), ¹H NMR δ 7.43 (d, 1H), 7.38 (d, 1H), 7.28 (dd, 1H), 3.66 (s, 3H),3.19 (d, J=10.7 Hz, 1H), 2.1-0.7 (m, 11H). Anal. (C₁₄H₁₈O₂Cl₂) C, H, Cl.

(2-Naphthyl)-(tetrahydropyran-2-yl) acetic acid methyl esters.

2-Naphthyl acetic acid (24.5 g, 0.132 mol) was dissolved in methanol(180 mL) and concentrated H₂SO₄ (2 mL) was added. The mixture was warmedto 45° C. and stirred for 18 h. It was then cooled to 22° C. andneutralized with NaHCO₃ to pH 7. Methanol was removed by evaporation,and H₂O (150 mL) was added. It was extracted with EtOAc (300 mL×3). Thecombined organic phase was dried (Na₂SO₄), filtered and evaporated todryness. Distillation (130° C., 0.5 mm Hg. 84%) furnished a white solid(22.0 g). ¹H NMR δ 7.88-7.78 (m, 3H), 7.72 (s, 1H), 7.53-7.39 (m, 3H),3.80 (s, 2H), 3.71 (s, 3H). The ester prepared above (2.0 g, 10.0 mmol)was dissolved in anhydrous THF (15 mL) and added dropwise to a cold (0°C.) LDA solution (5.0 mL, 2.0 M in heptane:THF:ethyl benzene 1:2:1.5)and stirred for 2 h at 0° C. The mixture was cooled to −78° C., and2-chlorotetrahydropyran (1.2 g, 10 mmol) in THF (5 mL) was addeddropwise. The reaction mixture was stirred at −78° C. for 1 h, thenslowly warmed to 22° C. and stirred overnight (17 h). THF was removed invacuo and H₂O (20 mL) was added. The crude product was extracted withEt₂O (50 mL×3). The combined Et₂O phases were dried (Na₂SO₄), filtered,and evaporated. The light brown oil (3.2 g) was purified by columnchromatography (1% EtOAc in hexane) to provide the product (0.50 g,18%). ¹H NMR δ 7.88-7.78 (m, 4H), 7.53-7.41 (m, 3H), 4.10-3.98 (m, 2H),3.73 (s, 1H), 3.70 (s, 3H), 3.53 (td, J=11.6, 3.1 Hz, 1H), 1.9-1.0 (m,6H), Anal. (C₁₈H₂₀O₃.0.4H₂O)C, H, Cl.

Single-Crystal X-ray Analysis of (2S.2′S)-(3,4-Dichlorophenyl)-(tetrahydropyran-2-vi) acetic acid (3a)

Monoclinic crystals of 3a were obtained from pentane. A representativecrystal was selected and a data set was collected at room temperature.Pertinent crystal, data collection and refinement parameters: crystalsize, 0.56×0.40×0.22 mm; cell dimensions, a=11.988 (1) Å, b=8.222 (1) Å,c=14.539 (1) Å, α=90°, β=104.35(1)°, γ=90°; formula, C₁₃H₁₄Cl₂O₃;formula weight=289.14; volume=1388.4 (2) Å³; calculated density=1383Mg/m⁻³; space group ═P2(1); number of reflections=2231 of which 2048were considered independent (R_(int)=0.0185). Refinement method wasfull-matrix least-squares on F². The final R-indices were [I>2σ (I)]R1=0.0465, wR2=0.1263.

Single-Crystal X-ray Analysis of (2R,2′S)-(3,4-Dichlorophenyl)-(tetrahydropyran-2-yl) acetic acid (4b)p-nitrophenyl ester.

Orthorhombic crystals of the purified p-nitrophenyl ester of 4b wereobtained from 90% hexane/10% EtOAc. A representative crystal wasselected and a data set was collected at room temperature. Pertinentcrystal, data collection and refinement parameters: crystal size,0.49×0.08×0.06 mm; cell dimensions, a=6.844 (1) Å, b=11.516 (2) Å,c=23.922(6) Å, α=90°, β=90°, γ=90°; formula, C₁₉H₁₇Cl₂NO₅; formulaweight=410.24; volume=1885.3 (7) Å³; calculated density=1.445 Mg/m⁻³;space group ═P2₁2₁2₁; number of reflections=1580 of which 1529 wereconsidered independent (R_(int)=0.0215). Refinement method wasfull-matrix least-squares on F². The final R-indices were [I>2σ (1)]R1=0.0504, wR_(2=0.1190.)

III. In Vitro Binding Assays

The affinities and transporter selectivities of the drugs were assessedin brain tissue of adult cynomolgus or rhesus monkey (Macaca fasicularisor Macaca Mulatta). Caudate -putamen was the source of the dopamine andserotonin transporters. The dopamine transporter affinity was measuredwith [3H]WIN 35,428 ([3H]CFT), the serotonin transporter was measuredwith [3H]citalopram and the norepinephrine transporter was measured with[3H]nisoxetine. Affinities of selected compounds were also measured atthe human dopamine transporter in HEK-293 cells expressing the humandopamine transporter (hDAT).

A. Brain Tissue preparation.

Brain tissue was harvested from adult male and female cynomolgus (Macacafasicularis) or rhesus (Macaca Mulatta) monkeys euthanized in the courseof other research or after spontaneous death. Tissue was stored in thebrain bank at the New England Regional Primate Research Center at −85°C. The caudate-putamen (approximately 1.5 g) was dissected from coronalsections of brain. Each caudate-putamen was homogenized and usedseparately for dopamine and serotonin transporter assays. Prior tohomogenization, the thalamus from two brains was pooled and membraneswere prepared as described previously for norepinephrine transporterassays (Madras et al., Synapse, 22:231-232, 1998; Madras et al.,Synapse, 24:340-348, 1996). Briefly, the tissue was homogenized in 10volumes (w/v) of ice-cold Tris.HCl buffer (50 mM, pH 7.4 at 0-4° C.) andcentrifuged at 38,700×g for 20 min in the cold. The resulting pellet wasresuspended in 40 volumes of buffer, and the entire wash procedure wasrepeated twice. The membrane suspension (25 mg original wet weight oftissue/ml) was diluted to 12 mg/ml in buffer just prior to assay anddispersed with a Brinkmanm polytron (setting #5) for 15 sec. Preliminaryexperiments demonstrated that tissue washing enhanced [³H]WIN 35,428(CFT) binding in tissue homogenates or tissue sections (Canfield et al.,Synapse 6:189-194, 1990; Madras, et al., Mol. Pharmacol. 36:518 -524,1989). All experiments were conducted in triplicate and each experimentwas repeated in 2-4 individual tissue preparations.

B. Dopamine Transporter Assay to Measure Affinity of Candidate Compounds

Competition experiments to determine the affinities of drugs at [³H]WIN35,428 (CFT) binding sites at the dopamine transporter were conductedusing procedures previously reported (Madras et al., Mol. Pharmacol.36:518-524, 1989). Stock solutions of water-soluble drugs were dissolvedin water or buffer and stock solutions of other drugs were made in arange of ethanol/HCl solutions. Several of the drugs were sonicated topromote solubility. The stock solutions were diluted serially in theassay buffer and added (0.2 ml) to the assay medium as described above.Each serial dilution in buffer was examined to ensure that therelatively water-insoluble compounds did not precipitate out. Affinitiesof drugs for the dopamine transporter were conducted as follows:

Affinities of drugs for the dopamine transporter, labeled by [³H]CFT(Specific activity: approximately 80 Ci/mmol, NEN) were determined inexperiments by incubating tissue with a fixed concentration of [³H]CFTand a range of concentrations of unlabeled test drug. The assay tubesreceived, in Tris.HCl buffer (50 mM, pH 7.4 at 0-4° C.; NaCl 100 mM), ata final assay concentration: [³H]CFT (1 nM, 0.2 ml); test drug (1 pM-100TM, 0.2 ml or buffer), membrane preparation (0.2 ml, 1 mg original wetweight of tissue/ml). The 2 h incubation (0-4° C.) was initiated byaddition of membranes and terminated by rapid filtration over WhitmanGFB glass fiber filters pre-soaked for 1 hour in 0.1% bovine serumalbumin (Sigma Chem. Co.). The filters were washed twice with 5 mlTris.HCl buffer (50 mM), incubated overnight at 0-4° C. in scintillationfloor (Beckman Ready-Value, 5 ml) and radioactivity was measured byliquid scintillation spectrometry. Cpm were converted to dpm followingdetermination of counting efficiency (49-53%) of each vial by externalstandardization. Total binding was defined as [³H]CFT bound in thepresence of ineffective concentrations of test drug (0.1-10 TM).Non-specific binding was defined as [³H]CFT bound in the presence of anexcess (30 TM) of (−)cocaine. Specific binding was the differencebetween the two values. In the caudate-putamn total binding of [³H]CFTranged from 1,500-3,500 dpm, and specific binding was approximately 90%of total.

The affinity of ([³H]CFT) for the dopamine transporter was determined inexperiments by incubating tissue with a fixed concentration of [³H]CFTand a range of concentrations of unlabeled CFT. The assay tubesreceived, in Tris.HCl buffer (50 mM, pH7.4 at 0-4° C.; NaCl 100 mM), thefollowing constituents at a final assay concentration: CFT, 0.2 ml (1pM-100 or 300 nM), [³H]CFT (0.3 nM); membrane preparation 0.2 ml (4 mgoriginal wet weight of tissue/ml).

C. Serotonin Transporter Assay to Measure Affinity of CandidateCompounds

The serotonin transporter was assayed in caudate-putamen membranes usingsimilar assay conditions as for the dopamine transporter. The assayswere conducted sideby-side to ensure that comparisons of the relativepotencies of the drugs at the two transporters were similar. Theaffinity of drugs for the serotonin transporter labeled by[³H]citalopram (spec. act.: approximately 85 Ci/mmol, NEN) wasdetermined in experiments by incubating tissue with a fixedconcentration of [³H]citalopram and a range of concentrations of drug.Assays were conducted in Tris-HCl buffer containing NaCl (100 mM) andthe following constituents: [³H]citalopram (1 nM, 0.2 ml), test drug (1pM-100 TM, 0.2 ml) and tissue (0.2 ml, 3 mg/ml original wet tissueweight). The 2 h incubation (0-4° C.) was initiated by addition ofmembranes and terminated by rapid filtration over Whatman GF/B glassfiber filters pre-soaked 1 hour in 0.1% polyethyleneimine. The filterswere washed three times with 5 ml Tris.HCl buffer (50 mM), and theremaining steps were carried out as described above. Total binding wasdefined as [³H]citalopram bound in the presence of ineffectiveconcentrations of unlabeled citalopram (1 pM) or the test compounds.Non-specific binding was defined as [³1H]citalopram bound in thepresence of an excess (10 TM) of fluoxetine. Specific binding was thedifference between the two values. Cpm were converted to dpm followingdetermination of counting efficiency (>45%) of each vial by externalstandardization.

D. Norepinephrine Transporter Assay

The norepinephrine transporter was assayed in thalamus membranes usingconditions similar to those for the serotonin transporter and adaptedfrom whole rat brain (Gehlart et al., J. Neurochem. 64:2792, 1995). Theaffinity of [³H]nisoxetine (spec. act.: 74 Ci/mmol, NEN) for thenorepinephrine transporter was determined in experiments by incubatingtissue with a fixed concentration of [³H]nisoxetine and a range ofconcentrations of unlabeled nisoxetine. The assay tubes received thefollowing constituents at a final assay concentration: nisoxetine ordrug (0.2 ml; 1 pM-300 TM), [³H]nisoxetine (0.2 ml; 0.6 nM); membranepreparation (0.2 ml; 4 mg original wet weight of tissue/ml). The bufferin the assay medium was Tris-HCl: 50 mM, pH 7.4 at 0-4° C.; NaCl 300 mM.The 16 h incubation at 0-4° C. was initiated by addition of membranesand terminated by rapid filtration over Whatman GF/B glass fiber filterspre-soaked in 0.3% polyethyleneimine for 1 h. The remaining steps aredescribed above. Total binding was defined as [³H]nisoxetine bound inthe presence of ineffective concentrations of drug. Non-specific bindingwas defined as [¹H]nisoxetine bound in the presence of an excess (10 TM)of desipramine. Specific binding was the difference between the twovalues.

E. Dopamine Transporter Assay in Cell Lines Expressing the HumanDopamine transporter

HDAT Cell Line (HEK-293) Preparation.

A full length human DAT cDNA isolated from a human substantia nigra cDNAlibrary was ligated into pcDNA3.1 (InVitrogen), resulting in an humandopamine transporter expression vector, peDNA3.1/hDAT. HEK293 cells weregrown in DMEM (BRL) supplemented with 10% fetal bovine serum (BR-L), 100U/ml penicillin, 100:g streptomycin (BRL), and 0.1 mm non-essentialamino acids (BRL), at 5% CO₂ in a 37° C. water-jacketed incubator.pcDNA3.1/hDAT (2 Tg) was transfected into HEK-293 cells withLipofectamine Reagent (BRL) according to the manufacturer's protocol.Following geneticin selection selection, single cells were replated into12 well plates. At confluence, monoclonal cell lines were replated andassayed for [³H].

The clone that displayed the highest dopamine uptake was selected andexpanded for study of dopamine uptake.

Affinities of Drugs for Blocking [³H]Dopamine Transport in HEK-293CellsExpressing the Human Dopamine Transporter (hDAT).

Low passage number cells (<25) plated at 80-90% confluency in 145 mmdishes were used for [³H]dopamine transport studies. The medium wasremoved by aspiration, and cells were washed with Tris-Hepes buffer, pH7.4 at 25° C. (Tris base: 5 mM, Hepes: 8.5 mM, NaCl: 120 mM, KCl: 5.4mM, CaCl₂:1.2 mM, MgSO₄:1.2 mM and glucose: 10 mM. The cells wereharvested, centrifuged at 125 g for 5 min, washed twice with theTris-Hepes buffer and diluted to 1,250,000 cells/ml. The intact cellsuspension (0.2 ml) was preincubated in triplicate with various drugdilutions for 15 min. Dopamine transport was initiated by the additionof [³H]dopamine (0.2 ml; DuPont-NEN, Boston, Mass.) for 10 min, at 25°C. The specific activity of the radioactive dopamine was 27.5 Ci/mM.Transport was terminated by filtration (Brandel, Gaithersburg, Md.) andtwo rapid washes with 5 ml of cold Tris-Hepes buffer over GF/B glassfiber filters (Whatman, Maidstone, UK) presoaked in 0.1%polyethylenimine (Sigma, St-Louis, Mo.). Bound radioactivity wasmeasured by liquid scintillation (Wallac, Gaithersburg, Md.)spectrometry (LS60001C, Beckman, Fullerton, Calif.). Nonspecific uptakewas defined as the uptake in the presence of 30 TM (−) cocaine, andthese data were subtracted from total counts to yield specificaccumulation of [³H]dopamine. The experiments were performed intriplicate and each value is the mean±S.E. of 2-5 independentexperiments. Protein concentrations were determined by Bradford assay(Bio-Rad, Richmond, Calif.).

Affinities of Drugs for the Dopamine Transporter, Labeled with [³H]CFTin HEK-293 Cells Expressing the Human Dopamine Transporter.

Similar intact cell suspension (0.2 ml) in buffer with tropolone (100TM) were used for [³H]CFT binding studies. In triplicate, variousdilution of drugs (0.2 ml; 10pM to 10 TM) were incubated with 1 nM[³H]CFT (0.2 ml; 80 Ci/mmol; NEN, Boston, Mass.) for 2 hours, at 4° C.Binding was terminated and measured as described above. Nonspecificbinding was defined in the presence of 30 TM (−) cocaine, and these datawere subtracted from total counts to yield total counts to yieldspecific binding of [³H]CFT. The experiments were performed intriplicate and each value is the mean±S.E. of 2-5 independentexperiments. Competition analysis of [³H]CFT binding was performed withEBDA and LIGAND computer programs (Elsevier-Biosoft, Cambridge, U.K.)

F. Data analysis.

Data were analyzed by the EBDA and LIGAND computer software programsElsevierBiosoft, U.K.) Final estimates of IC₅₀ and nH values werecomputed by the EBDA program. Baseline values for the individual drugswere established by computer analysis, using the baseline drugs as aguide. The LIGAND program provided final parameter estimates for theaffinity of the radioligand (Kd) by iterative non-linear curve-fittingand evaluation of one- or two-component binding models. LIGAND was usedto measure the affinity of the radioligands at the dopamine andserotonin transporter. Graphs (not shown) were produced by the computersoftware program PRISM, using a one- or two-site competition analysiscurve. TABLE 2 Affinity of selected compounds at the dopamine andserotonin transporters SERT DAT/SERT COMPOUND DAT IC₅₀ (nM) IC₅₀ (nM)RATIO Methylphenidate 17.2 ± 2.04 >100,000 5,800 0-1730 (threo 29.1 ±5.05 2,180 ± 226   75 diastereomer) 0-1731 (erythro 286 ± 10.5 7,795 ±1,840 27 diastereomer) 0-1783; 2b  17 ± 1.3 >10,000 >588 0-1792; 1b 193± 3.5  >10,000 >50 0-1793; 1a 736 ± 59  >10,000 >10 0-1794; 2a 33.9 ±8.6  1,655 ± 317   49 Indatraline 2.37 ± 0.11 — — 0-1630 Trans- 60 ± 23334 ± 100 6 geometry [3,4Cl₂Ph] 0-1618  104 ± 30.8 >3,000 >28 0-1629 116± 21  >3,400 >26 0-1617 Cis-geometry;  130 ± 49.7 >4,100 >32 [3,4Cl₂Ph]0-1833 Cis-geometry 189 ± 12  422 ± 38  2 [2-Naphthyl] 0-1925Trans-geometry 213 ± 27  136 ± 4.5  0.6 [2-Naphthyl] O-2075 118 6,650 56O-2078 104 2,480 24 O-2076 70 >5000 >70 O-2089 755 >10,000 >13 O-2098 251,400 56 Naphthyl mixture (12) 300 5,000 16.7  8 127 8,000 63  9 14612,000 82.2 10 128 10,000 78 11 47 7,000 149

The naphthyl compound 12, which is the analog of compound 1 and 2, hasan IC₅₀ of 300 nM. The carbocyclic analogs show surprising potency. Thecyclohexyl analogs, as either a methyl ester, 9, or a nitrile, 8,exhibit similar binding potency at the DAT (IC₅₀=127-146 nM) and SERT(IC₅₀=8-12 μM). While the cyclohexyl nitrile analog 10 is similarlypotent (IC₅₀=128 nM), the methyl ester 11 manifests substantial bindingpotency at the DAT (IC₅₀=47 nM) with substantial selectivity (150-fold)over the SERT.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A compound having the formula:

WHERE: * indicates a chiral center, and each chiral center,independently, may be R, S, or R/S; —X≡CH₂R₁; —CHR₁R₅; —CR₁═O; —CR₆═O;—O—R₁; —SR₁; —SOR₆; —SO₂R₆; —SO₂NHR₁; or —CH═CR₁R₅ and where: a. —R₁ and—R₅ are independently selected from: —H; —CH₃; —CH₂CH₃; or—CH₂(CH₂)_(m)CH₃, where m=0, 1, 2, or 3; PROVIDED THAT, when X≡O—R₁,then R₁ # H; and b. —R₆ is selected from: —OH; —OCH₃; —NHR₁; —O-alkyl;—O-alkenyl; —O-alkynyl; —O-allyl; —O-iodoallyl; -alkyl; -alkenyl;-alkynyl; -allyl; -isopropyl; and -isobutyl;. —Ar=either a) phenylsubstituted at any two positions with R_(3a) and R_(3b), where R_(3a)and R_(3b) are as defined in options “I.” or “II.”, below; or b)1-napththyl or 2-naphthyl, substituted at any two positions with R_(3a),and R_(3b) where R_(3a) and R_(3b) are as defined in option “I.”,below); OPTION I for R_(3a), and R_(3b) (phenyl or naphthylsubstitutions) —R_(3a) and —R_(3b) are independently selected from: —H;—Br; —Cl; —I; —F; —OH; —OCH₃; —CF₃; —NO₂; —NH₂; —CN; —NHCOCH₃, —C(CH₃)₃,—(CH₂)_(q)CH₃ where q=0-6; —COCH₃; —F (at the 2, 3 or 4 position), —Cl(at the 2, 3 or 4 position); —I (at the 2, 3 or 4 position); alkyl;alkenyl; alkenyl; allyl; iospropyl; isobutyl; alkyl; -alkylN₂S₂chelator;-alkylN₂S₂Tc chelator; or COR₇, where R₇ is defined below; OR OPTION II.for R_(3a) and R_(3b) (phenyl substitutions) —R_(3a) and —R_(3b) as apair are independently selected from the following pairs: 3,4-diCl;3,4,diOH; 3,4-diOAc; 3,4-diOCH₃; 3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; or3-F, 4-OH; n=0 or 1; —R₂=—H; —COOCH₃; —COR₇; -alkyl; -alkenyl; -allyl;-iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN₂S₂chelator-; —O-alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; —O-alkylN₂S₂Tcchelator; where, —R₇ is=—NHR₅; morpholinyl; piperidinyl; —CH₃; —CH₂CH₃;—CH₂(CH₂)_(r)CH₃ where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl;isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH₂SO₂; -alkylN₂S₂chelator; -alkylN₂S₂Tc chelator; O-alkylN₂S₂ chelator; or —O-alkylN₂S₂Tcchelator; and —R₈ is=-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl;-isoxazole; -oxadiazole; -oxazole; -alkylN₂S₂ chelator —O-alkylN₂S₂chelator; -alkylN₂S₂Tc chelator; or —O-alkylN₂S₂Tc chelator; R_(4a) andR_(4b) are independently selected from: —H; —Br; —Cl; —I; —F; —OH;—OCH₃; —CF₃; —NO₂; —NH₂; —CN; —NHCOCH₃, —C(CH₃)₃, —(CH₂)_(q)CH₃ whereq=0-6; —COCH₃; —F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4position); —I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl;allyl; iospropyl; isobutyl; alkyl; -alkylN₂S₂; -alkylN₂S₂Tc; and COR₇,where R₇ is defined above; or R_(4a) and R_(4b) are selected as a pairfrom the following pairs: 3,4-diCl; 3,4-diOH; 3,4-diOAc; 3,4-diOCH₃;3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; and 3-F, 4-OH.
 2. The compound ofclaim 1 in which n=0.
 3. The compound of claim 1 or claim 2 in whichX≡O—R₁.
 4. The compound of claim 3 in which —R₁═—CH₃.
 5. The compound ofclaim 1 in which Ar=1- or 2-naphthyl, substituted at any two positionswith R_(3a), and R_(3b), where R_(3a) and R_(3b) are as defined inoption “I.”, above.
 6. The compound of claim 5 in which R_(3a) andR_(3b) are both —H.
 7. The compound of claim 1 in which Ar=phenylsubstituted at any two positions with R_(3a), and R_(3b).
 8. Thecompound of claim 7 in which R_(3a), and R_(3b) are independentlyselected from —H and —Cl.
 9. The compound of claim 8 in which R_(3a),and R_(3b) are both —Cl.
 10. (canceled)
 11. A compound having theformula A, B, or C:

Where: n is 0, 1, 2, or 3; >X is >CH₂; >CHY, >C(Y,Z); >C═O; >O; >S; >SO;>SO₂; >NSO₂; >NSO₂R₃; or >C═CYZ; where Y and Z are independentlyselected from H; Br; Cl; I; F; OH; OCH₃; CF₃; NO₂; NH₂; CN; NHCOCH₃;N(CH₃)₂; (CH₂)_(n)CH₃, where m=0-6; COCH₃; alkyl alkenyl, alkynyl,allyl, isopropyl, isobutyl; —Ar=either a) phenyl substituted at any twopositions with R_(1a) and R_(1b), where R_(1a) and R_(1b) are as definedin options “I.” or “II.”, below; or b) 1-napththyl or 2-naphthyl,substituted at any two positions with R_(1a) and R_(1b) where R_(1a) andR_(1b) are as defined in option “I.”, below); OPTION I for R_(1a), andR_(1b) (phenyl or naphthyl substitutions) —R_(1a) and —R_(1b) areindependently selected from: —H; —Br; —Cl; —I; —F; —OH; —OCH₃; —CF₃;—NO₂; —NH₂; —CN; —NHCOCH₃, —C(CH₃)₃, —(CH₂)_(q)CH₃ where q=0-6; —COCH₃;—F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (atthe 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl;isobutyl; alkyl; -alkylN₂S₂ chelator; -alkylN₂S₂Tc chelator; or COR₄,where R₄ is defined below; OR OPTION II. for R_(1a), and R_(1b) (phenylsubstitutions) —R_(1a) and —R_(1b) as a pair are independently selectedfrom the following pairs: 3,4-diCl; 3,4,diOH; 3,4-diOAc; 3,4-diOCH₃;3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; or 3-F, 4-OH; —R₂=—COOCH₃; —COR₄;-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole;-oxazole; -alkylN₂S₂ chelator; —O-alkylN₂S₂ chelator; -alkylN₂S₂Tcchelator; —O-alkylN₂S₂Tc chelator; or

where, —R₄ is=—NHR₅; morpholinyl; piperidinyl; —CH₃; —CH₂CH₃;—CH₂(CH₂),CH₃ where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl;isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH₂SO₂; -alkylN₂S₂chelator; -alkylN₂S₂Tc chelator; O-alkylN₂S₂ chelator; or —O-alkylN₂S₂Tcchelator; and —R₅ is=-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl;-isoxazole; -oxadiazole; -oxazole; -alkylN₂S₂ chelator; —O-alkylN₂S₂chelator; -alkylN₂S₂Tc chelator; —O-alkylN₂S₂Tc chelator, and R₉ and R₁₀are independently ═H, CH₃, CH₂CH₃, (CH₂)_(r)CH₃, (CH₂)_(r)C₆H₃YZ,isopropyl, isobutyl, CH═CH—(CH₂)_(r)CH₃, CH₂CH═CH(CH₂)_(r)CH₃,(CH₂)_(s)CH═CH(CH₂)_(r)CH₃, C═C(CH₂)_(r)CH₃, CH₂C═C(CH₂)_(r)CH₃, wherer=0-6 and s=0-6 and Y and Z are independently ═H, F, Cl, Br, I, OH, OR,CH₃, CF₃, amino, NO₂.
 12. The compound of claim 11 in which X=O.
 13. Thecompound of claim 11 in which n=1.
 14. The compound of claim 11 in whichX═C.
 15. The compound of claim 11 in which X═C and n=0.
 16. The compoundof claim 11 in which the compound has formula A.
 17. The compound ofclaim 16 in which R₂ is selected from —COR₄ or —COOCH₃.
 18. The compoundof claim 16 in which —Ar=phenyl substituted at any two positions withR_(1a) and R_(1b).
 19. The compound of claim 18 in which R_(1a) andR_(1b) are independently selected from —H and —Cl.
 20. The compound ofclaim 19 in which R_(1a) and R_(1b) are each —Cl.
 21. (canceled)
 22. Acompound selected from compounds α-Cyclohexyl(3,4-dichlorobenzyl)cyanideand 2,2-(3,4-Dichlorophenyl)cyclohexyl acetic acid methyl ester.
 23. Acompound selected from compounds α-cyclopentyl-3,4-dichlorobenzylcyanideand a-cyclopentyl-3,4-dichlorophenylcyclohexyl acetic acid methyl ester.24. The compound of claim 11 in which R₂=


25. A method for treating a patient by administering to the patient acompound according to claim 1 or claim 11 in a dose effective to inhibita monoamine transporter.
 26. A method of treating a medical conditioncomprising administering to a patient a compound according to claim 1 orclaim 11, said medical condition being attention deficit hyperactivitydisorder (ADHD), Parkinson's disease, cocaine addiction, smokingcessation, weight reduction, obsessive-compulsive disorder, variousforms of depression, traumatic brain injury, stroke, and narcolepsy. 27.A method of making a medicament for treating attention deficithyperactivity disorder (ADHD), Parkinson's disease, cocaine addiction,smoking cessation, weight reduction, obsessive-compulsive disorder,various forms of depression, traumatic brain injury, stroke, andnarcolepsy, said method comprising formulating a compound according toclaim 1 or claim 11 into said medicament.
 28. A method of treating amedical condition comprising administering to a patient a compoundaccording to claim 1 or claim 11, said medical condition beingdepression and related disorders, seasonal affective disorders, sexualdysfunction, sexual behavior disorders, attention deficit hyperactivitydisorder, learning deficit, senile dementia, disorders involving therelease of acetylcholine, including memory deficits, dementia of aging,AIDS-dementia, senile dementia, pseudodementia, presenile dementia),autism, mutism, cognitive disorders, dyslexia, tardive dyskinesia,hyperkinesia, anxiety, panic disorders, paranoia, post-traumaticsyndrome, social phobia, other phobias, psychosis, bipolar disorder andother psychiatric or clinical disfunctions, mania, manic depression,schizophrenia (deficient form and productive form) and acute or chronicextrapyramidal symptoms induced by neuroleptic agents, obsessivecompulsive disorders (OCD), chronic fatigue syndrome, for enhancingalertness, attention, arousal and vigilance, narcolepsy, disorders ofsleep, jet-lag, obesity, bulimic and other eating disorders, anorexianervosa, cocaine and other drug addiction or misuse, alcoholism, tobaccoabuse, neurological disorders including epilepsy, traumatic braininjury, treatment of neurodegenerative diseases, including Parkinson'sDisease, Alzheimer's Disease, Huntington's Disease, Amyotrophic LateralSclerosis, Gilles de la Tourette's syndrome, the treatment of mild,moderate or even severe pain of acute, chronic or recurrent character,as well as pain caused by migraine, postoperative pain, and phantom limbpain, disorders linked to decreased transmission of serotonin inmammals, including Ganser's syndrome, migraine headache, pre-menstrualsyndrome or late luteal phase syndrome, and peripheral neuropathy.
 29. Apharmaceutical composition comprising a compound according to claim 1 orclaim 11 mixed with a pharmaceutically acceptable carrier.
 30. A methodof visualizing monoamine transport activity comprising exposing cells toa compound according to claim 1 or claim 11, and visualizing thepresence of the compound.
 31. A method according to claim 30 in whichthe compound is labeled to aid visualization.
 32. The method of claim 31in which the label is a radiolabel.
 33. The method of claim 31 in whichthe method is diagnostive of a medical indication involving monoaminetransport.
 34. The method of claim 33 in which the medical indication isdepression and related disorders, seasonal affective disorders, sexualdysfunction, sexual behavior disorders, attention deficit hyperactivitydisorder, learning deficit, senile dementia, disorders involving therelease of acetylcholine, including memory deficits, dementia of aging,AIDS-dementia, senile dementia, pseudodementia, presenile dementia),autism, mutism, cognitive disorders, dyslexia, tardive dyskinesia,hyperkinesia, anxiety, panic disorders, paranoia, post-traumaticsyndrome, social phobia, other phobias, psychosis, bipolar disorder andother psychiatric or clinical disfunctions, mania, manic depression,schizophrenia (deficient form and productive form) and acute or chronicextrapyramidal symptoms induced by neuroleptic agents, obsessivecompulsive disorders (OCD), chronic fatigue syndrome, for enhancingalertness, attention, arousal and vigilance, narcolepsy, disorders ofsleep, jet-lag, obesity, bulimic and other eating disorders, anorexianervosa, cocaine and other drug addiction or misuse, alcoholism, tobaccoabuse, neurological disorders including epilepsy, traumatic braininjury, treatment of neurodegenerative diseases, including Parkinson'sDisease, Alzheimer's Disease, Huntington's Disease, Amyotrophic LateralSclerosis, Gilles de la Tourette's syndrome, the treatment of mild,moderate or even severe pain of acute, chronic or recurrent character,as well as pain caused by migraine, postoperative pain, and phantom limbpain, disorders linked to decreased transmission of serotonin inmammals, including Ganser's syndrome, migraine headache, pre-menstrualsyndrome or late luteal phase syndrome, and peripheral neuropathy.